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Find video protocols related to scientific articles indexed in Pubmed.
Glucagon-like peptide 1 stimulates insulin secretion via inhibiting RhoA/ROCK signaling and disassembling glucotoxicity-induced stress fibers.
Endocrinology
PUBLISHED: 09-22-2014
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Chronic hyperglycemia leads to pancreatic ?-cell dysfunction characterized by diminished glucose-stimulated insulin secretion (GSIS), but the precise cellular processes involved are largely unknown. Here we show that pancreatic ?-cells chronically exposed to a high glucose level displayed substantially increased amounts of stress fibers compared to ?-cells cultured at a low glucose level. ?-cells at high glucose were refractory to glucose-induced actin cytoskeleton remodeling and insulin secretion. Importantly, F-actin depolymerization by either Cytochalasin B or Latrunculin B restored glucotoxicity-diminished GSIS. The effects of glucotoxicity on increasing stress fibers and reducing GSIS were reversed by Y-27632, a ROCK specific inhibitor, which caused actin depolymerization and enhanced GSIS. Notably, GLP-1, a peptide hormone that stimulates GSIS at both normal and hyperglycemic conditions, also reversed glucotoxicity-induced increase of stress fibers and reduction of GSIS. In addition, GLP-1 inhibited glucotoxicity-induced activation of RhoA/ROCK, thereby resulted in actin depolymerization and potentiation of GSIS. Furthermore, this effect of GLP-1 was mimicked by cAMP-increasing agents Forskolin and IBMX, as well as the PKA agonist 6-Bnz-cAMP; whereas abolished by the PKA inhibitor Rp-cAMPS. To establish a clinical relevance of our findings, we examined the association of genetic variants of RHOA/ROCK with metabolic traits in MAGIC. Several single nucleotide polymorphisms (SNPs) in and around RHOA were associated with elevated fasting insulin and HOMA-IR, suggesting a possible role in metabolic dysregulation. Collectively, these findings unravel a novel mechanism whereby GLP-1 potentiates glucotoxicity-diminished GSIS by depolymerising F-actin cytoskeleton via PKA-mediated inhibition of the RhoA-ROCK signaling pathway.
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Dense network of one-dimensional midgap metallic modes in monolayer MoSe2 and their spatial undulations.
Phys. Rev. Lett.
PUBLISHED: 08-08-2014
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We report the observation of a dense triangular network of one-dimensional (1D) metallic modes in a continuous and uniform monolayer of MoSe(2) grown by molecular-beam epitaxy. High-resolution transmission electron microscopy and scanning tunneling microscopy and spectroscopy studies show that these 1D modes are midgap states at inversion domain boundaries. Scanning tunneling microscopy and spectroscopy measurements further reveal intensity undulations of the metallic modes, presumably arising from the superlattice potentials due to the moiré pattern and the quantum confinement effect. A dense network of the metallic modes with a high density of states is of great potential for heterocatalysis applications. The interconnection of such midgap 1D conducting channels may also imply new transport behaviors distinct from the 2D bulk.
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Critical roles of TIPE2 protein in murine experimental colitis.
J. Immunol.
PUBLISHED: 06-27-2014
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Both commensal bacteria and infiltrating inflammatory cells play essential roles in the pathogenesis of inflammatory bowel disease. The molecular mechanisms whereby these pathogenic factors are regulated during the disease are not fully understood. We report in this article that a member of the TNF-?-induced protein 8 (TNFAIP8) family called TIPE2 (TNFAIP8-like 2) plays a crucial role in regulating commensal bacteria dissemination and inflammatory cell function in experimental colitis induced by dextran sodium sulfate (DSS). Following DSS treatment, TIPE2-deficient mice, or chimeric mice that are deficient in TIPE2 only in their hematopoietic cells, lost less body weight and survived longer than wild-type controls. Consistent with this clinical observation, TIPE2-deficient mice exhibited significantly less severe colitis and colonic damage. This was associated with a marked reduction in the colonic expression of inflammatory cytokines, such as TNF-?, IL-6, and IL-12. Importantly, the ameliorated DSS-induced colitis in TIPE2(-/-) mice also was associated with reduced local dissemination of commensal bacteria and a weaker systemic inflammatory response. Combined with our previous report that TIPE2 is a negative regulator of antibacterial immunity, these results indicate that TIPE2 promotes colitis by inhibiting mucosal immunity to commensal bacteria.
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Global gene expression profiling identifies ALDH2, CCNE1 and SMAD3 as potential prognostic markers in upper tract urothelial carcinoma.
BMC Cancer
PUBLISHED: 06-16-2014
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Current knowledge about the molecular properties and prognostic markers of upper tract urothelial carcinoma (UTUC) is sparse and often based on bladder urothelial carcinoma (UC), which is thought to share common risk factors with UTUC. However, studies have suggested that differences exist regarding tumor behavior and molecular biology of these cancers, comprehensive investigations are needed to guide the clinical management of UTUC. In recent years, massively parallel sequencing has allowed insights into the biology of many cancers, and molecular prognostic markers based on this approach are rapidly emerging. The goal of this study was to characterize the gene expression patterns of UTUC using massively parallel sequencing, and identify potential molecular markers for prognosis in patients with UTUC.
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The functional and mechanistic relatedness of EZH2 and menin in hepatocellular carcinoma.
J. Hepatol.
PUBLISHED: 04-29-2014
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The alterations of histone modification may serve as a promising diagnostic biomarker of hepatocellular carcinoma (HCC), but the clinical and mechanistic relatedness of the histone H3 lysine 27 and 4 trimethylation (H3K27me3 and H3K4me3) in HCC remains poorly understood. Here we propose that the combination of H3K27me3 and H3K4me3 is a more precise predictive/prognostic value for outcome of HCC patients.
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Harnessing the hidden antitumor power of the MLL-AF4 oncogene to fight leukemia.
Cancer Cell
PUBLISHED: 04-17-2014
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It is unclear whether the antiproliferative/proapoptotic activity of oncogenes can be pharmacologically reactivated in cancer cells. In this issue of Cancer Cell, Liu and colleagues report that a proteasome inhibitor reactivates an MLL-AF4 controlled antitumor program to kill leukemia cells in an oncogene dose- and cell type-dependent manner.
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Resiniferatoxin for treatment of lifelong premature ejaculation: a preliminary study.
Int. J. Urol.
PUBLISHED: 03-30-2014
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To evaluate the efficacy of resiniferatoxin in the treatment of patients with lifelong premature ejaculation.
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Glucagon-like peptide 1-potentiated insulin secretion and proliferation of pancreatic ?-cells.
J Diabetes
PUBLISHED: 03-28-2014
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Glucagon-like peptide-1 (GLP-1) is the primary incretin hormone secreted from the intestine upon uptake of food to stimulate insulin secretion from pancreatic ?-cells. GLP-1 exerts its effects by binding to its G-protein coupled receptors and subsequently activating adenylate cyclase, leading to generation of cyclic adenosine monophosphate (cAMP). cAMP stimulates insulin secretion via activation of its effectors PKA and Epac2 in pancreatic ?-cells. In addition to its insulinotropic effects, GLP-1 also preserves pancreatic ?-cell mass by stimulating ?-cell proliferation. Unlike the action of sulphonylureas in lowering blood glucose levels, action of GLP-1 is affected by and interplays with glucose levels. Due to such advantages, GLP-1-based therapeutics have been rapidly developed and used clinically for treatment of type 2 diabetes. However, molecular mechanisms underlying how GLP-1 potentiates diminished glucose-stimulated insulin secretion and ?-cell proliferation under diabetic conditions are not well understood. Here, we review the actions of GLP-1 in regulation of insulin secretion and pancreatic ?-cell proliferation.
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The efficacy and safety of docetaxel plus thalidomide vs. docetaxel alone in patients with androgen-independent prostate cancer: a systematic review.
Sci Rep
PUBLISHED: 03-19-2014
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The aim of this systematic review was taken to investigate the efficacy and safety of docetaxel plus thalidomide vs. docetaxel alone for treating androgen-independent prostate cancer (AIPC). Data were collected from different databases independently by three researchers according to the pre-defined inclusion and exclusion criteria. Total three studies were finally included, indicating that docetaxel plus thalidomide exhibited better survival prognosis and greater prostate-specific antigen (PSA) decline than docetaxel alone. There were no significant differences of hematologic toxicities in two regimens, while the frequency of non-hematologic toxicities was higher in patients with docetaxel plus thalidomide. Briefly, the available evidence indicates potential survival advantage in docetaxel plus thalidomide over docetaxel alone.
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Identification of Hsf1 as a novel androgen receptor-regulated gene in mouse Sertoli cells.
Mol. Reprod. Dev.
PUBLISHED: 03-03-2014
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Androgen signaling plays a crucial role in spermatogenesis, yet few downstream targets for this signaling pathway have been identified. In the current study, we found that the expression of heat-shock transcription factor 1 (Hsf1) was increased in the testes of Sertoli cell-selective androgen receptor knockout (S-AR(-/y) ) mice compared with wild-type mice by quantitative real-time PCR, and the expression of HSF1 in the S-AR(-/y) Sertoli cells was significantly increased, based on immunofluorescence analysis. In vitro cell-culture studies showed that testosterone repressed the expression of Hsf1 in TM4 cells, a mouse Sertoli cell line. Moreover, a luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay showed that testosterone repressed Hsf1 expression by facilitating the binding of androgen receptor to the Hsf1 promoter. Our experiments also demonstrated that testosterone-mediated inhibition of Hsf1 transcription down-regulated the expression of heat-shock proteins HSP105 and HSP60. Taken together, these results reveal that Hsf1 is a novel target of androgen receptor in mouse Sertoli cells, and testosterone and its receptor regulate the process of spermatogenesis partially by inhibiting Hsf1 expression.
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Menin is required for optimal processing of the microRNA let-7a.
J. Biol. Chem.
PUBLISHED: 02-21-2014
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Multiple endocrine neoplasia type I (MEN1) is an inherited syndrome that includes susceptibility to pancreatic islet hyperplasia. This syndrome results from mutations in the MEN1 gene, which encodes menin protein. Menin interacts with several transcription factors, including JunD, and inhibits their activities. However, the precise mechanism by which menin suppresses gene expression is not well understood. Here, we show that menin interacts with arsenite-resistant protein 2 (ARS2), a component of the nuclear RNA CAP-binding complex that is crucial for biogenesis of certain miRNAs including let-7a. The levels of primary-let-7a (pri-let-7a) are not affected by menin; however, the levels of mature let-7a are substantially decreased upon Men1 excision. Let-7a targets, including Insr and Irs2, pro-proliferative genes that are crucial for insulin-mediated signaling, are up-regulated in Men1-excised cells. Inhibition of let-7a using anti-miRNA in wild type cells is sufficient to enhance the expression of insulin receptor substrate 2 (IRS2) to levels observed in Men1-excised cells. Depletion of menin does not affect the expression of Drosha and CBP80, but substantially impairs the processing of pri-miRNA to pre-miRNA. Ars2 knockdown decreased let-7a processing in menin-expressing cells but had little impact on let-7a levels in menin-excised cells. As IRS2 is known to mediate insulin signaling and insulin/mitogen-induced cell proliferation, these findings collectively unravel a novel mechanism whereby menin suppresses cell proliferation, at least partly by promoting the processing of certain miRNAs, including let-7a, leading to suppression of Irs2 expression and insulin signaling.
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Mixed adenocarcinoma, sarcomatoid carcinoma and adenosquamous carcinoma of the prostate: A case report.
Oncol Lett
PUBLISHED: 02-18-2014
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Adenosquamous carcinoma (ASC) and sarcomatoid carcinoma (SC) of the prostate are rare, but highly aggressive tumors. The occurrence of mixed carcinomas in the prostate is even more rarely reported. The present study reports the case of a 62-year-old male who was diagnosed with prostatic adenocarcinoma accompanied by multiple bone metastases, as shown by a needle biopsy and skeletal computed tomography scan. The patient was treated with hormonal therapy, but thereafter, specimens from a transurethral resection of the prostate (TURP) were found to be composed of three histologically distinct elements: ASC, SC and adenocarcinoma. The level of p53 was evaluated by immunohistochemistry in detail, and it was found that this was significantly increased in the TURP samples compared with the needle biopsy samples. The abnormal level of p53 was likely associated with the prognosis of the patient; the patient succumbed to prostate carcinoma two months after the confirmation of the diagnosis.
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MicroRNA-451a is associated with cell proliferation, migration and apoptosis in renal cell carcinoma.
Mol Med Rep
PUBLISHED: 02-15-2014
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MicroRNAs (miRNAs) are an important class of small, non?coding RNA molecules that regulate gene expression at the transcriptional or post?transcriptional level. They are involved in apoptosis, proliferation and migration and are known to have an important role in many types of cancer. Aberrant expression of miRNA?451a (miR?451a) has previously been reported in tumors, however its role in renal cell carcinoma (RCC) is currently unknown. The aim of the present study was to investigate the role of miR?451a in RCC. The expression of miR?451a was analyzed in 50 paired RCC and normal tissues by quantitative polymerase chain reaction. Furthermore, the effects of miR?451a on cell migration, proliferation and apoptosis were evaluated, using migration scratch, MTT and flow cytometric assays. The present study demonstrated that miR?451a was upregulated in RCC, as compared with paired normal tissues (P<0.05). Downregulation of miR?451a using a synthesized inhibitor, significantly suppressed cell migration and proliferation, and induced apoptosis of renal cancer cells in vitro, as compared with a negative control (P<0.05). In the present study, it was determined that miR?451a may have an important role as a tumor enhancer in RCC. These results imply that miR?451a may be a promising therapeutic target for the treatment of RCC.
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CMTM3 inhibits human testicular cancer cell growth through inducing cell-cycle arrest and apoptosis.
PLoS ONE
PUBLISHED: 01-01-2014
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Human CMTM3 has been proposed as a putative tumor suppressor gene. The loss of CMTM3 has been found in several carcinomas. However, the regulation of CMTM3 expression and its function in tumor progression remain largely unknown. Here, we investigated the regulation of CMTM3 expression, function and molecular mechanism in human testicular cancer cells. CMTM3 was frequently downregulated or silenced in testicular cancer cell lines and tumor tissues but highly expressed in normal testis tissues. The re-expression of CMTM3 significantly suppressed the colony formation, proliferation, and migration capacity of testicular cancer cells by inducing a G2 cell cycle arrest and apoptosis. Moreover, the re-expression of CMTM3 activated the transcription of p53, induced p53 accumulation, up-regulated the expression of p21, and increased the cleavage of caspase 9, 8, 3, and PARP. The downregulation of CMTM3 in clinical tumor tissues was associated with the methylation of a single CpG site located within the Sp1/Sp3-responsive region of the core promoter. These results indicate that CMTM3 can function as tumor suppressor through the induction of a G2 cell cycle arrest and apoptosis. CMTM3 is thus involved in testicular cancer pathogenesis, and it is frequently at least partially silenced by the methylation of a single, specific CpG site in tumor tissues.
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Telomerase Reverse Transcriptase Gene Promoter Mutations Help Discern the Origin of Urogenital Tumors: A Genomic and Molecular Study.
Eur. Urol.
PUBLISHED: 10-18-2013
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Activation of telomerase can be observed in almost all human tumor histotypes and detection of the urinary telomerase activities is useful for the diagnosis and surveillance of bladder cancer. In this study, we screened, by Sanger sequencing, 302 patients with various urogenital cancers for somatic mutations in the promoter of the telomerase reverse transcriptase (TERT) gene and determined the clinical relevance of TERT promoter mutations in urogenital cancer. In vitro assays were also performed to evaluate the functional influence of the discovered mutations. We found that the frequencies of somatic mutations in the TERT promoter varied substantially between different types of urogenital tumors (range: 0-63.7%), with urothelial carcinomas showing the highest mutation frequency and prostate cancer showing no mutation. The mutations upregulated the expression of TERT and enhanced the invasiveness of the tumor cells. The mutations were more prevalent in older patients with invasive diseases and advanced tumor stages, and were associated with significantly shorter survival time. Moreover, we also observed a significant co-occurrence of mutations between the TERT promoter and the tumor protein 51/retinoblastoma1 (TP53/RB1) signaling pathway. Hence, TERT promoter mutations may serve as important markers for the differential diagnosis and surveillance of urogenital tumors.
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Menin directly represses Gli1 expression independent of canonical Hedgehog signaling.
Mol. Cancer Res.
PUBLISHED: 08-08-2013
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Multiple endocrine neoplasia type 1 (MEN-1), is a familial tumor syndrome resulting from mutations in the tumor suppressor gene menin (MEN1). Menin plays an essential role in both repressing and activating gene expression. However, it is not well understood how menin represses expression of multiple genes. Upon MEN1 excision, the transcription factor Gli1 and its target genes, including Ptch1 and c-Myc, were shown to be elevated in the absence of an apparent Hedgehog) pathway-activating ligand or when Smoothened (SMO), a key component of the pathway, is inhibited. Menin binds to the GLI1 promoter and recruits PRMT5, a histone arginine methyltransferase associated with transcriptional repression. Both PRMT5 binding and histone H4 arginine 3 methylation (H4R3m2s) are decreased at the GLI1 promoter in MEN1-excised cells. Moreover, MEN1 ablation resulted in increased binding of transcriptionally active Gli1 at the GLI1 promoter in a manner not influenced by the canonical Hedgehog signaling pathway. Inhibition of Gli1 by the small-molecule inhibitor GANT-61 led to decreased expression of Gli1 and its target genes in MEN1-depeleted cells. Furthermore, GANT-61 potently suppressed proliferation of MEN1-excised cells as compared with control cells. These findings uncover a novel epigenetic link whereby menin directly represses Gli1 expression, independent of the canonical Hedgehog signaling pathway, via PRMT5 and its repressive H4R3m2s mark.
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Identification of miR-7 as an oncogene in renal cell carcinoma.
J. Mol. Histol.
PUBLISHED: 04-23-2013
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MicroRNA-7 (miR-7) has been described as a tumor suppressor in several human cancers, but the results of a study to identify miRNAs associated with metastatic capability in breast cancer suggested that miR-7 may be characterized as an oncogene. The present study was to determine the expression and function of miR-7 in renal cell carcinoma. Quantitative real-time polymerase chain reaction was used to validate the expressions of miR-7 in 48 paired renal cell carcinomas (RCC) and normal tissues, based on the preliminary sequencing results of miRNAs. Furthermore, the impacts of miR-7 on cell migration, proliferation and apoptosis were analyzed using wound scratch assay, MTT and flow cytometry, respectively. The results demonstrated that miR-7 was up-regulated in RCC compared with normal tissues (p = 0.001). Down-regulation of miR-7 with synthesized inhibitor inhibited cell migration in vitro, suppressed cell proliferation and induced renal cancer cell apoptosis, prompting that miR-7 could be characterized as an oncogene in RCC. The present study was the first to reveal that miR-7 was up-regulated in RCC and it played an important role in RCC by affecting cellular migration, proliferation and apoptosis. Further researches should be conducted to explore the roles and target genes of miR-7 in RCC and other cancers.
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Cascaded silicon-on-insulator double-ring sensors operating in high-sensitivity transverse-magnetic mode.
Opt Lett
PUBLISHED: 04-19-2013
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We demonstrate ultrahigh-sensitivity silicon photonic sensors based on two cascaded double-ring resonators operating in transverse-magnetic mode. Both wavelength interrogation and intensity interrogation methods are experimentally investigated and the sensitivities reached 24,300 nm/RIU and 2430 dB/RIU, respectively. We also show that the double-ring sensors can be simply cascaded to realize simultaneous detection of multiple species, which is very promising for low-cost array applications.
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Menin epigenetically represses Hedgehog signaling in MEN1 tumor syndrome.
Cancer Res.
PUBLISHED: 04-11-2013
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Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumor syndrome that includes susceptibility to pancreatic islet tumors. This syndrome results from mutations in the MEN1 gene, encoding menin. Although menin acts as an oncogenic cofactor for mixed lineage leukemia (MLL) fusion protein-mediated histone H3 lysine 4 methylation, the precise basis for how menin suppresses gene expression and proliferation of pancreatic beta cells remains poorly understood. Here, we show that menin ablation enhances Hedgehog signaling, a proproliferative and oncogenic pathway, in murine pancreatic islets. Menin directly interacts with protein arginine methyltransferase 5 (PRMT5), a negative regulator of gene transcription. Menin recruits PRMT5 to the promoter of the Gas1 gene, a crucial factor for binding of Sonic Hedgehog (Shh) ligand to its receptor PTCH1 and subsequent activation of the Hedgehog signaling pathway, increases repressive histone arginine symmetric dimethylation (H4R3m2s), and suppresses Gas1 expression. Notably, MEN1 disease-related menin mutants have reduced binding to PRMT5, and fail to impart the repressive H4R3m2s mark at the Gas1 promoter, resulting in its elevated expression. Pharmacologic inhibition of Hedgehog signaling significantly reduces proliferation of insulinoma cells, and expression of Hedgehog signaling targets including Ptch1, in MEN1 tumors of mice. These findings uncover a novel link between menin and Hedgehog signaling whereby menin/PRMT5 epigenetically suppresses Hedgehog signaling, revealing it as a target for treating MEN1 tumors.
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Positive words or negative words: whose valence strength are we more sensitive to?
Brain Res.
PUBLISHED: 04-10-2013
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The present study investigates the human brains sensitivity to the valence strength of emotionally positive and negative chinese words. Event-Related Potentials were recorded, in two different experimental sessions, for Highly Positive (HP), Mildly Positive (MP) and neutral (NP) words and for Highly Negative (HN), Mildly Negative (MN) and neutral (NN) words, while subjects were required to count the number of words, irrespective of word meanings. The results showed a significant emotion effect in brain potentials for both HP and MP words, and the emotion effect occurred faster for HP words than MP words: HP words elicited more negative deflections than NP words in N2 (250-350 ms) and P3 (350-500 ms) amplitudes, while MP words elicited a significant emotion effect in P3, but not in N2, amplitudes. By contrast, HN words elicited larger amplitudes than NN words in N2 but not in P3 amplitudes, whereas MN words produced no significant emotion effect across N2 and P3 components. Moreover, the size of emotion-neutral differences in P3 amplitudes was significantly larger for MP compared to MN words. Thus, the human brain is reactive to both highly and mildly positive words, and this reactivity increased with the positive valence strength of the words. Conversely, the brain is less reactive to the valence of negative relative to positive words. These results suggest that human brains are equipped with increased sensitivity to the valence strength of positive compared to negative words, a type of emotional stimuli that are well known for reduced arousal.
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Identification and characterization of OsEBS, a gene involved in enhanced plant biomass and spikelet number in rice.
Plant Biotechnol. J.
PUBLISHED: 03-22-2013
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Common wild rice (Oryza rufipogon Griff.) is an important genetic reservoir for rice improvement. We investigated a quantitative trait locus (QTL), qGP5-1, which is related to plant height, leaf size and panicle architecture, using a set of introgression lines of O. rufipogon in the background of the Indica cultivar Guichao2 (Oryza sativa L.). We cloned and characterized qGP5-1 and confirmed that the newly identified gene OsEBS (enhancing biomass and spikelet number) increased plant height, leaf size and spikelet number per panicle, leading to an increase in total grain yield per plant. Our results showed that the increased size of vegetative organs in OsEBS-expressed plants was enormously caused by increasing cell number. Sequence alignment showed that OsEBS protein contains a region with high similarity to the N-terminal conserved ATPase domain of Hsp70, but it lacks the C-terminal regions of the peptide-binding domain and the C-terminal lid. More results indicated that OsEBS gene did not have typical characteristics of Hsp70 in this study. Furthermore, Arabidopsis (Arabidopsis thaliana) transformed with OsEBS showed a similar phenotype to OsEBS-transgenic rice, indicating a conserved function of OsEBS among plant species. Together, we report the cloning and characterization of OsEBS, a new QTL that controls rice biomass and spikelet number, through map-based cloning, and it may have utility in improving grain yield in rice.
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Menin: a scaffold protein that controls gene expression and cell signaling.
Trends Biochem. Sci.
PUBLISHED: 03-19-2013
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The protein menin is encoded by the MEN1 gene, which is mutated in patients with multiple endocrine neoplasia type 1 (MEN1) syndrome. Although menin acts as a tumor suppressor in endocrine organs, it is required for leukemic transformation in mouse models. Menin possesses these dichotomous functions probably because it can both positively and negatively regulate gene expression, as well as interact with a multitude of proteins with diverse functions. Here, we review the recent progress in understanding the molecular mechanisms by which menin functions. The crystal structures of menin with different binding partners reveal that menin is a key scaffold protein that functionally crosstalks with various partners to regulate gene transcription and interplay with multiple signaling pathways.
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The trithorax protein partner menin acts in tandem with EZH2 to suppress C/EBP? and differentiation in MLL-AF9 leukemia.
Haematologica
PUBLISHED: 01-24-2013
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Trithorax and polycomb group proteins antagonistically regulate the transcription of many genes, and cancer can result from the disruption of this regulation. Deregulation of trithorax function occurs through chromosomal translocations involving the trithorax gene MLL, leading to the expression of MLL fusion proteins and acute leukemia. It is poorly understood how MLL fusion proteins block differentiation, a hallmark of leukemogenesis. We analyzed the effect of acute depletion of menin, a close partner of MLL that is critical for MLL and MLL-AF9 recruitment to target genes, on MLL-AF9 leukemia cell differentiation using an in vivo model. We performed cDNA microarray analysis of menin-regulated genes from primary leukemia cells to determine menin-regulated pathways involved in suppressing MLL-AF9 leukemia cell differentiation. We found that menin binds the promoter of the polycomb gene Ezh2, and promotes its expression. EZH2 interacts with the differentiation-promoting transcription factor C/EBP? and represses C/EBP? target genes. Menin depletion reduces MLL binding to the Ezh2 locus, EZH2 expression, and EZH2 binding and repressive H3K27 methylation at C/EBP? target genes, thereby inducing the expression of pro-differentiation C/EBP? targets. In conclusion, our results show that in contrast to its classical role antagonizing trithorax function, the polycomb group protein EZH2 collaborates with trithorax-associated menin to block MLL-AF9 leukemia cell differentiation, uncovering a novel mechanism for suppression of C/EBP? and leukemia cell differentiation, through menin-mediated upregulation of EZH2.
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Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation.
Nat. Genet.
PUBLISHED: 01-15-2013
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Bladder cancer is one of the most common cancers worldwide, with transitional cell carcinoma (TCC) being the predominant form. Here we report a genomic analysis of TCC by both whole-genome and whole-exome sequencing of 99 individuals with TCC. Beyond confirming recurrent mutations in genes previously identified as being mutated in TCC, we identified additional altered genes and pathways that were implicated in TCC. Notably, we discovered frequent alterations in STAG2 and ESPL1, two genes involved in the sister chromatid cohesion and segregation (SCCS) process. Furthermore, we also detected a recurrent fusion involving FGFR3 and TACC3, another component of SCCS, by transcriptome sequencing of 42 DNA-sequenced tumors. Overall, 32 of the 99 tumors (32%) harbored genetic alterations in the SCCS process. Our analysis provides evidence that genetic alterations affecting the SCCS process may be involved in bladder tumorigenesis and identifies a new therapeutic possibility for bladder cancer.
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Increased expression of pregnancy up-regulated non-ubiquitous calmodulin kinase is associated with poor prognosis in clear cell renal cell carcinoma.
PLoS ONE
PUBLISHED: 01-01-2013
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The aims of this study were to evaluate the clinical significance and potential prognostic value of pregnancy up-regulated non-ubiquitous calmodulin kinase (PNCK) in clear cell renal cell carcinoma (ccRCC) patients.
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Menin represses malignant phenotypes of melanoma through regulating multiple pathways.
J. Cell. Mol. Med.
PUBLISHED: 08-30-2011
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Substantial genetic evidence suggests that chromosome 11q is involved in regulating initiation and progression of malignant melanomas. Mutations of the MEN1 gene, located in chromosome 11q13, predispose individuals to the multiple endocrine neoplasia type 1 (MEN1) familial syndrome. MEN1 patients develop primary malignant melanoma, suggesting a potential link between MEN1 syndrome and development of melanomas, but the precise molecular mechanism is poorly understood. Here we show that the MEN1 gene suppresses malignant phenotypes of melanoma cells through multiple signalling pathways. Ectopic expression of menin, the product of MEN1 gene, significantly inhibited melanoma cell proliferation and migration in vitro and in vivo. The inhibition was partly achieved through suppressing expression of growth factor pleiotrophin (PTN) and receptor protein tyrosine phosphatase (RPTP) ?/?, accompanied with the reduced expression of phosphatidylinositol 3-kinase (pI3K) and decreased phosphorylation of focal adhesion kinase (FAK) and extracellular signal regulated kinase (ERK1/2). Interestingly, reduced expression of menin was associated with hypermethylation of the CpG islands of the MEN1 promoter in melanoma cells. Taken together, these findings suggest a previously unappreciated function for menin in suppressing malignant phenotypes of melanomas and unravel a novel mechanism involving in regulating PTN signalling by menin in development and progression of melanomas.
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Genome-wide microRNA profiles identify miR-378 as a serum biomarker for early detection of gastric cancer.
Cancer Lett.
PUBLISHED: 07-28-2011
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Recent studies demonstrated that in several human malignancies aberrant expression profiles of circulating microRNAs (miRNAs) anticipate great cancer diagnostic potential. Here we showed that serum miR-378 could serve as a novel noninvasive biomarker in gastric cancer (GC) detection. Genome-wide miRNA expression profiles followed with Real-Time quantitative RT-PCR (qRT-PCR) assays revealed that miR-187(*), miR-371-5p and miR-378 were significantly elevated in GC patients. Further validation indicated that miR-378 alone could yields a ROC curve area of 0.861 with 87.5% sensitivity and 70.73% specificity in discriminating GC patients from healthy controls. Collectively, these data support our contention that serum miR-378 has strong potential as a novel noninvasive biomarker in gastric cancer detection.
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Systemic activation of K-ras rapidly induces gastric hyperplasia and metaplasia in mice.
Am J Cancer Res
PUBLISHED: 07-16-2011
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Mouse models with conditional activation of K-ras (K-ras(G12D)) are used widely to investigate the role of oncogenic K-ras in a tissue-specific manner. However, the effect of ubiquitous activation of K-ras in adult mice has not been well studied. Herein, we report that systemic activation of K-ras in mice leads to rapid changes in gastric cellular homeostasis. Conditional activation of K-ras results in activation of the MAPK pathway and hyperproliferation of squamous epithelium in the forestomach and metaplasia in the glandular stomach. Parietal cells almost completely disappear from the upper part of the stomach adjacent to forestomach of K-ras activated mice. CDX2, a caudal-related homeobox transcription factor normally expressed in the intestine, is upregulated in parts of the stomach, following activation of K-ras in mice. Cyclooxygenase 2 (COX-2), a mediator of inflammation, is also upregulated in parts of the stomach of the K-ras activated mice with concomitant infiltration of hematopoietic cells in the hyperplastic tissue. Moreover, in K-ras activated mice, the expression of putative progenitor cell marker Dcamkl1 is upregulated in the glandular stomach. Expression of CD44, a candidate stomach cancer stem cell marker, is also increased in forestomach and the glandular stomach. These results suggest that cells of the stomach, potentially stem or progenitor cells, are highly susceptible to K-ras activation-induced initiation of gastric precancerous lesions. The histological changes in the K-ras activated mice resemble the pre-neoplastic changes that take place during gastric carcinogenesis in humans. Thus, a mouse model with systemic K-ras(G12D) activation could be useful for studying the early molecular events leading to gastric carcinogenesis.
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A systematic analysis on DNA methylation and the expression of both mRNA and microRNA in bladder cancer.
PLoS ONE
PUBLISHED: 07-05-2011
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DNA methylation aberration and microRNA (miRNA) deregulation have been observed in many types of cancers. A systematic study of methylome and transcriptome in bladder urothelial carcinoma has never been reported.
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The impact of emotion valence on brain processing of behavioral inhibitory control: spatiotemporal dynamics.
Neurosci. Lett.
PUBLISHED: 06-10-2011
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Emotion is known to interact with behavioral inhibitory control (BIC), an ability critical for adaptive living. Nevertheless, how emotion valence influences this control, and the spatiotemporal dynamics underlying this influence, remain undetermined. For this purpose, the present study recorded event-related potentials (ERPs) for a standard stimulus which required no BIC, and for deviant stimuli that required controlling habitual responses during pleasant, neutral and unpleasant blocks. Behavioral results showed prolonged reaction times (RTs) and diminished accuracy rates for deviant than for standard stimuli, irrespective of the emotionality of deviants. Moreover, there were significant main effects of stimulus type, and significant stimulus and emotion interaction effects on the averaged amplitudes of the 200-300ms and 300-500ms intervals. Through analyzing the deviant-standard difference ERPs that index BIC directly, we found larger N2 and smaller P3 amplitudes during the unpleasant block than during the neutral block. The pleasant block, in contrast, showed a trend of more pronounced P3 amplitudes than the neutral block. Thus, by synchronizing BIC with emotion induction, we found distinct impact of pleasant and unpleasant emotions on behavioral inhibitory processing, not only in early monitoring of response conflicts but also in the late stage of response inhibition.
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Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma.
Nat. Genet.
PUBLISHED: 06-03-2011
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We sequenced whole exomes of ten clear cell renal cell carcinomas (ccRCCs) and performed a screen of ?1,100 genes in 88 additional ccRCCs, from which we discovered 12 previously unidentified genes mutated at elevated frequencies in ccRCC. Notably, we detected frequent mutations in the ubiquitin-mediated proteolysis pathway (UMPP), and alterations in the UMPP were significantly associated with overexpression of HIF1? and HIF2? in the tumors (P = 0.01 and 0.04, respectively). Our findings highlight the potential contribution of UMPP to ccRCC tumorigenesis through the activation of the hypoxia regulatory network.
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Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder.
Nat. Genet.
PUBLISHED: 05-13-2011
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Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.
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Menin represses tumorigenesis via repressing cell proliferation.
Am J Cancer Res
PUBLISHED: 04-20-2011
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Multiple endocrine neoplasia type 1 (MEN1) results from mutations in the tumor suppressor gene, MEN1, which encodes nuclear protein menin. Menin is important for suppressing tumorigenesis in various endocrine and certain non-endocrine tissues. Although menin suppresses MEN1 through a variety of mechanisms including regulating apoptosis and DNA repair, the role of menin in regulating cell proliferation is one of the best-studied functions. Here, we focus on reviewing various mechanisms underlying menin-mediated inhibition of cell proliferation. Menin inhibits cell proliferation to repress MEN1 through multiple mechanisms. 1) Menin interacts with various histonemodifying enzymes, such as MLL, EZH2 and HDACs, to affect gene transcription, leading to repression of cell proliferation. 2) Menin also interacts with various transcription factors, such as JunD, NF-?B, PPAR? and VDR, to induce or suppress gene transcription. As these various transcription factors are known to regulate cell proliferation, their interaction with menin may be relevant to menins role in inhibiting cell proliferation. 3) Menin inhibits cell proliferation via TGF-? signaling and Wnt/?-catenin signaling pathways. 4) Menin represses certain pro-proliferative factors involved in endocrine tumors such as IGFBP-2, IGF2 and PTHrP to repress cell proliferation. 5) Menin affects cell cycle progression to inhibit cell proliferation. This review is helpful in our understanding of the comprehensive mechanisms whereby menin represses MEN1 through inhibiting cell proliferation.
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Comparative mRNA and microRNA expression profiling of three genitourinary cancers reveals common hallmarks and cancer-specific molecular events.
PLoS ONE
PUBLISHED: 04-07-2011
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Genome-wide gene expression profile using deep sequencing technologies can drive the discovery of cancer biomarkers and therapeutic targets. Such efforts are often limited to profiling the expression signature of either mRNA or microRNA (miRNA) in a single type of cancer.
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Decreased expression of dual-specificity phosphatase 9 is associated with poor prognosis in clear cell renal cell carcinoma.
BMC Cancer
PUBLISHED: 03-20-2011
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The molecular mechanisms involved in the development and progression of clear cell renal cell carcinomas (ccRCCs) are poorly understood. The objective of this study was to analyze the expression of dual-specificity phosphatase 9 (DUSP-9) and determine its clinical significance in human ccRCCs.
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The valence strength of unpleasant emotion modulates brain processing of behavioral inhibitory control: neural correlates.
Biol Psychol
PUBLISHED: 03-16-2011
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As an ability critical for adaptive social living, behavioral inhibitory control (BIC) is known to be influenced substantially by unpleasant emotion. Nevertheless, how unpleasant emotion of diverse strength influences this control, and the spatiotemporal dynamics underlying this influence, remain undetermined. For this purpose, Event-related potentials (ERPs) were recorded for standard stimulus which required no BIC, and for deviant stimuli that required controlling habitual responses, during highly unpleasant (HU), mildly unpleasant (MU) and Neutral blocks. The results showed delayed response latencies for deviant compared to standard stimuli, irrespective of emotionality. Moreover, there were significant main effects of stimulus type, and significant stimulus type and block interaction effects on the averaged amplitudes of the 230-310 ms and 330-430 ms intervals. In the deviant-standard difference waves which directly index BIC-relevant processing, these interactions were manifested by increased negative potentials as a function of the strength of unpleasant emotion across N2 and P3 components. In addition, these influences are specific to unpleasant emotion, as pleasant emotion of diverse strength produced a similar impact in the control experiment. Therefore, unpleasant emotion of diverse strength is different in impact on brain processing of behavioral inhibitory control. This impact is evident not only in early monitoring of response conflicts, but also in late processing of response inhibition.
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Tumor suppressor menin represses paired box gene 2 expression via Wilms tumor suppressor protein-polycomb group complex.
J. Biol. Chem.
PUBLISHED: 03-04-2011
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Tumor suppressor menin, the product of the MEN1 gene, plays a key role in controlling histone 3 lysine 4 trimethylation (H3K4me3) and gene transcription, which can regulate proliferation, apoptosis, and differentiation. However, little is known as to whether menin controls gene expression and cell proliferation and survival via regulating Polycomb group (PcG) protein complex/H3K27me3. Here we show that menin specifically represses transcription factor Paired box gene 2 (Pax2) through PcG-mediated H3K27me3 and Wilms tumor suppressor protein (WT1), a zinc finger domain-containing DNA-binding protein. Menin does not directly bind to the Pax2 locus, instead, it up-regulates WT1 expression. WT1 recruits PcG complex to the Pax2 promoter and represses expression of Pax2 through PcG-dependent H3K27me3. Moreover, WT1 also interacts with DNA methyltransferase 1 (DNMT1), and recruits DNMT1 to the Pax2 promoter, resulting in hypermethylation of CpG in the Pax2 promoter. Together, these studies have uncovered a novel epigenetic mechanism whereby menin regulates H3K27me3 and promoter DNA methylation via WT1 and suggest that WT1 protein plays an important, yet previously unappreciated role in regulating the function of the menin/PcG axis, H3K27 methylation, and DNA methylation, resulting in repression of gene transcription.
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MicroRNA expression signatures of bladder cancer revealed by deep sequencing.
PLoS ONE
PUBLISHED: 03-02-2011
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MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression. They are aberrantly expressed in many types of cancers. In this study, we determined the genome-wide miRNA profiles in bladder urothelial carcinoma by deep sequencing.
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Epigenetic inactivation of PCDH10 in human prostate cancer cell lines.
Cell Biol. Int.
PUBLISHED: 02-15-2011
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PCDH10 (protocadherin-10), a novel tumour suppressor gene, is down-regulated in several human cancers due to hypermethylation of promoter CGIs (CpG islands). Here, we investigated the expression of PCDH10 in different normal adult tissues and in a panel of prostate cancer cell lines. PCDH10 was widely expressed in normal tissues with higher levels in the prostate. The expression of PCDH10 was markedly reduced or silenced in prostate cancer cell lines compared with normal adult prostate tissue. Decreased PCDH10 expression was correlated with the methylation status of the PCDH10 promoter. Furthermore, the DNA demethylating agent 5-azacytidin restored PCDH10 expression by suppressing PCDH10 promoter methylation in prostate cancer cell lines. Treatment with Trichostatin A alone had no significant effect on the expression of PCDH10 but enhanced the effect of 5-azacytidin. In conclusion, we found that the decreased PCDH10 expression in prostate cancer cells was associated with the aberrant methylation of PCDH10 promoter CGI. Our results may contribute to the understanding of the role of PCDH10 inactivation in the progression of prostate cancers.
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Identification of heterotic loci associated with yield-related traits in Chinese common wild rice (Oryza rufipogon Griff.).
Plant Sci.
PUBLISHED: 01-08-2011
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Many rice breeding programs have currently reached yield plateaus as a result of limited genetic variability in parental strains. Dongxiang common wild rice (Oryza rufipogon Griff.) is the progenitor of cultivated rice (Oryza sativa L.) and serves as an important gene pool for the genetic improvement of rice cultivars. In this study, heterotic loci (HLs) associated with six yield-related traits were identified in wild and cultivated rice and investigated using a set of 265 introgression lines (ILs) of O. rufipogon Griff. in the background of the Indica high-yielding cultivar Guichao 2 (O. sativa L.). Forty-two HLs were detected by a single point analysis of mid-parent heterosis values from test cross F(1) offspring, and 30 (71.5%) of these HLs showed significantly positive effects, consistent with the superiority shown by the F(1) test cross population in the six yield-related traits under study. Genetic mapping of hsp11, a locus responsible for the number of spikelets per panicle, confirmed the utility of these HLs. The results indicate that favorable HLs capable of improving agronomic traits are available. The identification of HLs between wild rice and cultivated rice could lead to a new strategy for the application of heterosis in rice breeding.
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Identification and characterization of human PCDH10 gene promoter.
Gene
PUBLISHED: 01-03-2011
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Recent studies have suggested roles for PCDH10 as a novel tumor suppressor gene. In our previous work, we located the core promoter of PCDH10 to a 462-bp segment of 5-flanking region characterized by a high GC content. Here we further identified and characterized the promoter for PCDH10. Transient transfection of PC3 and LNCaP cells with a series of deleted promoter constructs indicated that the minimal promoter region was between nucleotides -144 and -99. This segment contained a CAAT box, a GT box, and a putative transcription factor binding site for AP-4. Mutational analysis identified that the CAAT box and GT box are necessary for promoter activity. Ectopic expression of NF-Ys increased reporter gene activity, whereas expression of a dominant-negative NF-YA decreased reporter gene activity. Co-transfection of Sp1/Sp3 expression plasmids enhanced reporter gene activity in a dose-dependent manner. Mithramycin A, an inhibitor of Sp-DNA interaction, reduced PCDH10 promoter activity. Electrophoretic mobility shift assays and chromatin immunoprecipitation demonstrated binding of transcription factors Sp1/Sp3 to the promoter region in vitro and in vivo. Our data show that Sp1/Sp3 and CBF/NF-Y transcription factors play a crucial role in the basal expression of the human PCDH10 gene.
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Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 11-08-2010
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A hallmark of diabetes is an absolute or relative reduction in the number of functional ? cells. Therapies that could increase the number of endogenous ? cells under diabetic conditions would be desirable. Prevalent gene targeting mouse models for assessing ?-cell proliferation and diabetes pathogenesis only address whether deletion of a gene prevents the development of diabetes. Models testing whether acute excision of a single gene can ameliorate or reverse preexisting hyperglycemia in established diabetes remain to be explored, which could directly validate the effect of gene excision on treating diabetes. Here, we report that acute and temporally controlled excision of the Men1 gene, which encodes menin, ameliorated preexisting hyperglycemia in streptozotocin-treated mice. Moreover, Men1 excision also improved the preexisting hyperglycemia and glucose intolerance in genetic db/db diabetic mice. Furthermore, acute Men1 excision reversed preexisting glucose intolerance in high-fat diet-fed mice. Men1 excision improved glucose metabolism at least partly through increasing proliferation of endogenous ? cells and islet size. Acute Men1 excision up-regulated a group of proproliferative genes in pancreatic islets. Together, these findings demonstrate that established hyperglycemia can be reversed through repression of a single gene, Men1, in diabetic conditions, and suggest that menin is a vital regulator in pathogenesis of diabetes.
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Deletion of the Men1 gene prevents streptozotocin-induced hyperglycemia in mice.
Exp Diabetes Res
PUBLISHED: 09-16-2010
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Diabetes ultimately results from an inadequate number of functional beta cells in the islets of Langerhans. Enhancing proliferation of functional endogenous beta cells to treat diabetes remains underexplored. Here, we report that excision of the Men1 gene, whose loss-of-function mutation leads to inherited multiple endocrine neoplasia type 1 (MEN1), rendered resistant to streptozotocin-induced hyperglycemia in a tamoxifen-inducible and temporally controlled Men1 excision mouse model as well as in a tissue-specific Men1 excision mouse model. Men1 excision prevented mice from streptozotocin-induced hyperglycemia mainly through increasing the number of functional beta cells. BrdU incorporation by beta cells, islet size, and circulating insulin levels were significantly increased in Men1-excised mice. Membrane localization of glucose transporter 2 was largely preserved in Men1-excised beta cells, but not in Men1-expressing beta cells. Our findings suggest that repression of menin, a protein encoded by the Men1 gene, might be a valuable means to maintain or increase the number of functional endogenous beta cells to prevent or ameliorate diabetes.
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Observing photophysical properties of quantum dots in air at the single molecule level: advantages in microarray applications.
Lab Chip
PUBLISHED: 08-17-2010
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Quantum dots (QDs) are promising fluorescent tags for microarrays. Because most microarrays are analyzed under dry conditions, it is necessary to examine the photo properties of QDs in air. We demonstrate that the photophysical characteristics of individual quantum dots are different at the liquid/solid interface compared with QDs at the air/solid interface by observing them through a wide-field fluorescence microscope. QDs in air show higher photo-stability, higher fluorescence signal, slower spectral blue shift rate, less blinking and shorter bulk fluorescence lifetime than those in solution. These beneficial properties indicate QDs are good alternative fluorescent probes for microarrays.
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Integrated profiling of microRNAs and mRNAs: microRNAs located on Xq27.3 associate with clear cell renal cell carcinoma.
PLoS ONE
PUBLISHED: 08-04-2010
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With the advent of second-generation sequencing, the expression of gene transcripts can be digitally measured with high accuracy. The purpose of this study was to systematically profile the expression of both mRNA and miRNA genes in clear cell renal cell carcinoma (ccRCC) using massively parallel sequencing technology.
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Regulation of cyclin B2 expression and cell cycle G2/m transition by menin.
J. Biol. Chem.
PUBLISHED: 04-19-2010
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Multiple endocrine neoplasia type 1 (MEN1) results from mutations in tumor suppressor gene Men1, which encodes nuclear protein menin. Menin up-regulates certain cyclin-dependent kinase inhibitors through increasing histone H3 lysine 4 (H3K4) methylation and inhibits G(0)/G(1) to S phase transition. However, little is known as to whether menin controls G(2)/M-phase transition, another important cell cycle checkpoint. Here, we show that menin expression delays G(2)/M phase transition and reduces expression of Ccnb2 (encoding cyclin B2). Menin associates with the promoter of Ccnb2 and reduces histone H3 acetylation, a positive chromatin marker for gene transcription, at the Ccnb2 locus. Moreover, Men1 ablation leads to an increase in cyclin B2 expression, histone H3 acetylation at the Ccnb2 locus, and G(2)/M transition. In contrast, knockdown of cyclin B2 diminishes the number of cells at M phase and reduces cell proliferation. Furthermore, menin interferes with binding of certain positive transcriptional regulators, such as nuclear factor Y (NF-Y), E2 factors (E2Fs), and histone acetyltransferase CREB (cAMP-response element-binding protein)-binding protein (CBP) to the Ccnb2 locus. Notably, MEN1 disease-related mutations, A242V and L22R, abrogate the ability of menin to repress cyclin B2 expression and G(2)/M transition. Both of the mutants fail to reduce the acetylated level of the Ccnb2 locus. Together, these results suggest that menin-mediated repression of cyclin B2 is crucial for inhibiting G(2)/M transition and cell proliferation through a previously unrecognized molecular mechanism for menin-induced suppression of MEN1 tumorigenesis.
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Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase.
Cancer Cell
PUBLISHED: 02-23-2010
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Cyclin D1 elicits transcriptional effects through inactivation of the retinoblastoma protein and direct association with transcriptional regulators. The current work reveals a molecular relationship between cyclin D1/CDK4 kinase and protein arginine methyltransferase 5 (PRMT5), an enzyme associated with histone methylation and transcriptional repression. Primary tumors of a mouse lymphoma model exhibit increased PRMT5 methyltransferase activity and histone arginine methylation. Analyses demonstrate that MEP50, a PRMT5 coregulatory factor, is a CDK4 substrate, and phosphorylation increases PRMT5/MEP50 activity. Increased PRMT5 activity mediates key events associated with cyclin D1-dependent neoplastic growth, including CUL4 repression, CDT1 overexpression, and DNA rereplication. Importantly, human cancers harboring mutations in Fbx4, the cyclin D1 E3 ligase, exhibit nuclear cyclin D1 accumulation and increased PRMT5 activity.
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MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele.
Cancer Cell
PUBLISHED: 02-18-2010
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Oncogenic fusion proteins are capable of initiating tumorigenesis, but the role of their wild-type counterparts in this process is poorly understood. The mixed lineage leukemia (MLL) gene undergoes chromosomal translocations, resulting in the formation of oncogenic MLL fusion proteins (MLL-FPs). Here, we show that menin recruits both wild-type MLL and oncogenic MLL-AF9 fusion protein to the loci of HOX genes to activate their transcription. Wild-type MLL not only catalyzes histone methylation at key target genes but also controls distinct MLL-AF9-induced histone methylation. Notably, the wild-type Mll allele is required for MLL-AF9-induced leukemogenesis and maintenance of MLL-AF9-transformed cells. These findings suggest an essential cooperation between an oncogene and its wild-type counterpart in MLL-AF9-induced leukemogenesis.
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Automatic processing of valence differences in emotionally negative stimuli: evidence from an ERP study.
Neurosci. Lett.
PUBLISHED: 06-30-2009
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The present study investigated the influence of attention on the human sensitivity to valence differences in emotionally negative stimuli. Event-related potentials were recorded for unattended highly negative (EN), moderately negative (MN) and neutral pictures in Experiment 1 which engaged subjects in an auditory discrimination task; and for EN, MN and neutral pictures in Experiment 2 that required visual classification of pictures. Results of both experiments displayed increased negative deflections during EN than during MN and neutral conditions at 150-250, 250-350, and 350-450 ms intervals post-stimulus. Moreover, MN stimuli elicited larger negativity than did neutral stimuli during 250-350 ms interval in either experiment. This developed our understanding of the human sensitivity to valence differences in negative stimuli, by revealing that the brain sensitivity to the valence strength of negative stimuli exists stably, unaffected by attention access to some extent.
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Neural correlates of the females susceptibility to negative emotions: an insight into gender-related prevalence of affective disturbances.
Hum Brain Mapp
PUBLISHED: 05-01-2009
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Considerable studies reported that females are more susceptible to affective disturbances such as depression, anxiety disorder, and phobia compared to males. Based on the close relation between emotional sensitivity and liability to affective disturbances (Hofer et al. [2006]: NeuroImage 32, 854-862; Spearing [2001]: Bipolar disorder, 2nd ed. Bethesda (MA): National institute of Mental Health), this study investigated the neural mechanism underlying the females liability to affective disturbances by hypothesizing that females are more susceptible to negative emotions than males. Event-related potentials (ERPs) were recorded for highly negative (HN), moderately negative (MN), and neutral images in Experiment 1, and for highly positive, moderately positive, and neutral images in Experiment 2, whereas subjects (15 males and 15 females) performed a standard/deviant distinction task, irrespective of the emotional valence of deviants in both experiments. In addition to the prominent emotional reactions evoked by HN stimuli in both genders, Experiment 1 displayed conspicuous emotional responses of females to MN stimuli across N2 and P3 components, which were absent in males. In contrast, Experiment 2 demonstrated neither significant valence effect, nor significant valence by gender interaction effect at these components. Thus, although both genders are sensitive to HN stimuli, females, instead of males, are particularly susceptible to negative stimuli of lesser salience, and this female specific susceptibility does not exist to the positive stimuli. Therefore, females must be more susceptible to negative emotions in life settings, which may be one important mechanism underlying their higher prevalence of affective disturbances.
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Menin regulates the function of hematopoietic stem cells and lymphoid progenitors.
Blood
PUBLISHED: 02-21-2009
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Men1 is a tumor suppressor gene mutated in endocrine neoplasms. Besides its endocrine role, the Men1 gene product menin interacts with the mixed lineage leukemia (MLL) protein, a histone H3 lysine 4 methyltransferase. Although menin and MLL fusion proteins cooperate to activate Homeobox (Hox) gene expression during transformation, little is known about the normal hematopoietic functions of menin. Here, we studied hematopoiesis after Men1 ablation. Menin loss modestly impaired blood neutrophil, lymphocyte, and platelet counts. Without hematopoietic stress, multilineage and myelo-erythroid bone marrow progenitor numbers were preserved, while B lymphoid progenitors were decreased. In contrast, competitive transplantation revealed a marked functional defect of long-term hematopoietic stem cells (HSC) in the absence of menin, despite normal initial homing of progenitors to the bone marrow. HoxA9 gene expression was only modestly decreased in menin-deficient HSCs. These observations reveal a novel and essential role for menin in HSC homeostasis that was most apparent during situations of hematopoietic recovery, suggesting that menin regulates molecular pathways that are essential during the adaptive HSC response to stress.
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High expression of FER tyrosine kinase predicts poor prognosis in clear cell renal cell carcinoma.
Oncol Lett
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FER tyrosine kinase (FER) has been demonstrated to play a critical role in tumorigenesis and metastasis; however, its potential value as a novel prognostic marker for clear cell renal cell carcinoma (ccRCC) remains unclear. In 48 paired samples of ccRCCs and normal adjacent tissues (ADTs), real-time PCR was used to evaluate the expression of FER mRNA. The expression of FER protein was assessed in 87 ADTs and 206 samples of ccRCC using immunohistochemical methods. Statistical analysis was used to examine the correlations between the expression levels of FER and the clinical characteristics of ccRCC patients. A significant difference was identified between ccRCC tissues and ADTs in the mRNA levels of FER. Immunohistochemistry analyses revealed higher expression of FER protein in 87 ccRCC samples compared to the paired ADTs. In addition, FER protein expression in 206 ccRCC samples was significantly correlated with tumor size, T stage, N classification, metastasis, recurrence and Fuhrman grade, while associations with age and gender were not identifed. The Kaplan-Meier survival analysis showed that patients with high FER levels had a poorer survival outcome compared with those with lower levels. The log-rank test demonstrated that the cumulative survival rates were significantly different between the two groups. The Cox regression analysis indicated that FER expression, N stage and distant metastasis were independent prognostic factors for overall survival of ccRCC patients. Our results indicate that overexpression of FER in tumor tissues predicts a poor prognosis of patients with ccRCC, and FER may serve as a novel prognostic marker for ccRCC.
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Sporadic renal haemangioblastoma: Case report and review of the literature.
Oncol Lett
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Haemangioblastoma is a benign tumour which generally occurs in a relatively restricted area of the central nervous system. Renal haemangioblastoma are extremely rare. We report a rare case of renal haemangioblastoma occurring in a 61-year-old male with a solid mass, which was detected during a routine examination. The patient was asymptomatic and abdominal computed tomography (CT) revealed a solid mass in the right kidney. No definitive preoperative diagnosis could be established. Surgical resection of the tumour revealed sporadic renal haemangioblastoma by pathological examination. The patient was followed up at 1 year without any problems. We also present a supplementary review of previously published cases and literature.
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A dominant-negative mutation of HSF2 associated with idiopathic azoospermia.
Hum. Genet.
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Idiopathic azoospermia (IA) is a severe form of male infertility due to unknown causes. The HSF2 gene, encoding the heat shock transcription factor 2, had been suggested to play a significant role in the spermatogenesis process since the Hsf2-knockout male mice showed spermatogenesis defects. To examine whether HSF2 is involved in the pathogenesis of IA in human, we sequenced all the exons of HSF2 in 766 patients diagnosed with IA and 521 proven fertile men. A number of coding mutations private to the patient group, which include three synonymous mutations and five missense mutations, were identified. Of the missense mutations, our functional assay demonstrated that one heterozygous mutation, R502H, caused a complete loss of HSF2 function and that the mutant suppressed the normal function of the wild-type (WT) allele through a dominant-negative effect, thus leading to the dominant penetrance of the mutant allele. These results support a role for HSF2 in the pathogenesis of IA and further implicate this transcription factor as a potential therapeutic target.
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Two origins of blastemal progenitors define blastemal regeneration of zebrafish lower jaw.
PLoS ONE
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Zebrafish possess a remarkable ability to regenerate complicated structures by formation of a mass of undifferentiated mesenchymal cells called blastema. To understand how the blastema retains the original structural form, we investigate cellular transitions and transcriptional characteristics of cell identity genes during all stages of regeneration of an amputated lower jaw. We find that mesenchymal blastema originates from multiple sources including nucleated blood cells, fibroblasts, damaged muscle cells and pigment cells. These cells are transformed into two populations of blastemal progenitors: foxi1-expression and isl1-expression, before giving rise to cartilage, bone, and muscle. Time point- based transcriptomal analysis of 45 annotated Hox genes reveal that five 3-end Hox genes and an equal number of 5-end Hox genes are activated largely at the stage of blastema reformation. RNA in situ hybridization shows that foxi1 and pax3a are respectively expressed in the presumptive mandible skeletal region and regenerating muscle at 5 dpa. In contrast, hoxa2b and hoxa11b are widely expressed with different domain in chondrogenic blastema and blastema mesenchyme. Knockdown foxi1 changes the expression patterns of sox9a and hoxa2b in chondrogenic blastema. From these results we propose that two origins of blastemal progenitors define blastema skeleton and muscle respecifications through distinct signaling pathways. Meanwhile, the positional identity of blastema reformation is implicated in mesenchymal segmentation and characteristic expression pattern of Hox genes.
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Interplay between menin and K-Ras in regulating lung adenocarcinoma.
J. Biol. Chem.
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MEN1, which encodes the nuclear protein menin, acts as a tumor suppressor in lung cancer and is often inactivated in human primary lung adenocarcinoma. Here, we show that the inactivation of MEN1 is associated with increased DNA methylation at the MEN1 promoter by K-Ras. On one hand, the activated K-Ras up-regulates the expression of DNA methyltransferases and enhances the binding of DNA methyltransferase 1 to the MEN1 promoter, leading to increased DNA methylation at the MEN1 gene in lung cancer cells; on the other hand, menin reduces the level of active Ras-GTP at least partly by preventing GRB2 and SOS1 from binding to Ras, without affecting the expression of GRB2 and SOS1. In human lung adenocarcinoma samples, we further demonstrate that reduced menin expression is associated with the enhanced expression of Ras (p < 0.05). Finally, excision of the Men1 gene markedly accelerates the K-Ras(G12D)-induced tumor formation in the Men1(f/f);K-Ras(G12D/+);Cre ER mouse model. Together, these findings uncover a previously unknown link between activated K-Ras and menin, an important interplay governing tumor activation and suppression in the development of lung cancer.
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Menin as a hub controlling mixed lineage leukemia.
Bioessays
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Mixed lineage leukemia (MLL) fusion protein (FP)-induced acute leukemia is highly aggressive and often refractory to therapy. Recent progress in the field has unraveled novel mechanisms and targets to combat this disease. Menin, a nuclear protein, interacts with wild-type (WT) MLL, MLL-FPs, and other partners such as the chromatin-associated protein LEDGF and the transcription factor C-Myb to promote leukemogenesis. The newly solved co-crystal structure illustrating the menin-MLL interaction, coupled with the role of menin in recruiting both WT MLL and MLL-FPs to target genes, highlights menin as a scaffold protein and a central hub controlling this type of leukemia. The menin/WT MLL/MLL-FP hub may also cooperate with several signaling pathways, including Wnt, GSK3, and bromodomain-containing Brd4-related pathways to sustain MLL-FP-induced leukemogenesis, revealing new therapeutic targets to improve the treatment of MLL-FP leukemias.
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Ketamine-associated urinary tract dysfunction: an underrecognized clinical entity.
Urol. Int.
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The use of ketamine as a recreational drug is on the increase among young adults attending clubs and parties. Recreational ketamine users have anecdotally reported increased lower urinary tract symptoms while using the substance.
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A microRNA panel to discriminate carcinomas from high-grade intraepithelial neoplasms in colonoscopy biopsy tissue.
Gut
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It is a challenge to differentiate invasive carcinomas from high-grade intraepithelial neoplasms in colonoscopy biopsy tissues. In this study, microRNA profiles were evaluated in the transformation of colorectal carcinogenesis to discover new molecular markers for identifying a carcinoma in colonoscopy biopsy tissues where the presence of stromal invasion cells is not detectable by microscopic analysis.
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The same pocket in menin binds both MLL and JUND but has opposite effects on transcription.
Nature
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Menin is a tumour suppressor protein whose loss or inactivation causes multiple endocrine neoplasia 1 (MEN1), a hereditary autosomal dominant tumour syndrome that is characterized by tumorigenesis in multiple endocrine organs. Menin interacts with many proteins and is involved in a variety of cellular processes. Menin binds the JUN family transcription factor JUND and inhibits its transcriptional activity. Several MEN1 missense mutations disrupt the menin-JUND interaction, suggesting a correlation between the tumour-suppressor function of menin and its suppression of JUND-activated transcription. Menin also interacts with mixed lineage leukaemia protein 1 (MLL1), a histone H3 lysine 4 methyltransferase, and functions as an oncogenic cofactor to upregulate gene transcription and promote MLL1-fusion-protein-induced leukaemogenesis. A recent report on the tethering of MLL1 to chromatin binding factor lens epithelium-derived growth factor (LEDGF) by menin indicates that menin is a molecular adaptor coordinating the functions of multiple proteins. Despite its importance, how menin interacts with many distinct partners and regulates their functions remains poorly understood. Here we present the crystal structures of human menin in its free form and in complexes with MLL1 or with JUND, or with an MLL1-LEDGF heterodimer. These structures show that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase (JNK)-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.