The last quarter of a century has witnessed remarkable progress in the understanding of phosphoinositide 3-kinases (PI3K) signalling and their involvement in different diseases such as cancer, diabetes and inflammation. Nevertheless, many questions remain open and among these the role of genetic and epigenetic regulation of PI3K isoforms is one of the most prominent. Emerging evidence Indicates that levels of isoforms can be modulated upon stimulation or in both physiological and pathological conditions including increased gene copy number and transcription regulation. In addition, an intriguing role for epigenetic regulation of PI3K expression, caused by mechanisms other than changes in the underlying DNA sequence, are starting to get appreciated. In this review, we summarize the genetic and epigenetic regulation of PI3Ks in physiology and the role played by their alterations in different diseases.
Pancreatic cancer has one of the poorest prognoses among all cancers partly because of its silent nature and tendency for late discovery but also because of its persistent resistance to chemotherapy. At present there are very limited treatment alternatives for pancreatic cancer, hence the need to develop novel and more efficient drugs. It is well known that mutations in K-Ras oncogene accumulate early in the disease progression and occur in almost all of pancreatic ductal adenocarcinomas (PDAC). A key downstream target of the Ras family is phosphoinositide 3-kinase (PI3K), the enzyme responsible for generation of 3-phosphorylated phosphoinositides and activation of Akt (Protein Kinase B/Akt). The PI3K/Akt pathway is involved in inhibition of apoptosis and stimulation of cell proliferation and it is has been estimated that at least 50% of all cancer types are related to deregulation of this signalling pathway. In this review we will discuss how the PI3K/Akt/mTOR signaling network is altered in pancreatic cancer and further give an overview of preclinical and clinical studies where this pathway has been targeted.
Phosphoinositide 3-kinase (PI3K) signaling is well established as important in cancer. To date most studies have been focused on the PI3K/p110? isoform, which has been found to be mutated in several different cancers. The aim of our study was to determine which specific PI3K isoforms are involved in pancreatic ductal adenocarcinoma (PDAC) and investigate the effects of these isoforms on proliferation, survival, and induction of Akt activation in pancreatic cancer cells.
The scattering response of epithelial cells to activation of the Met receptor tyrosine kinase represents one facet of an "invasive growth" program. It is a complex event that incorporates loss of cell-cell adhesion, morphological changes, and cell motility. Ubiquitination is a reversible posttranslational modification that may target proteins for degradation or coordinate signal transduction pathways. There are approximately 79 active deubiquitinating enzymes (DUBs) predicted in the human genome. Here, via a small interfering RNA (siRNA) library approach, we have identified 12 DUBs that are necessary for aspects of the hepatocyte growth factor (HGF)-dependent scattering response of A549 cells. Different phenotypes are evident that range from full loss of scattering, similar to receptor knockdown (e.g., USP30, USP33, USP47), to loss of cell-cell contacts even in the absence of HGF but defective motility (e.g., USP3, ATXN3L). The knockdowns do not incur defective receptor, phosphatidylinositol 3-kinase, or MAP kinase activation. Our data suggest widespread involvement of the ubiquitin system at multiple stages of the Met activation response, implying significant crosstalk with phosphorylation-based transduction pathways. Development of small-molecule inhibitors of particular DUBs may offer a therapeutic approach to contain metastasis.
Understanding the factors, which control ErbB2 and EGF receptor (EGFR) status in cells is likely to inform future therapeutic approaches directed at these potent oncogenes. ErbB2 is resistant to stimulus-induced degradation and high levels of over-expression can inhibit EGF receptor down-regulation. We now show that for HeLa cells expressing similar numbers of EGFR and ErbB2, EGFR down-regulation is efficient and insensitive to reduction of ErbB2 levels. Deubiquitinating enzymes (DUBs) may extend protein half-lives by rescuing ubiquitinated substrates from proteasomal degradation or from ubiquitin-dependent lysosomal sorting. Using a siRNA library directed at the full complement of human DUBs, we identified POH1 (also known as Rpn11 or PSMD14), a component of the proteasome lid, as a critical DUB controlling the apparent ErbB2 levels. Moreover, the effects on ErbB2 levels can be reproduced by administration of proteasomal inhibitors such as epoxomicin used at maximally tolerated doses. However, the extent of this apparent loss and specificity for ErbB2 versus EGFR could not be accounted for by changes in transcription or degradation rate. Further investigation revealed that cell surface ErbB2 levels are only mildly affected by POH1 knock-down and that the apparent loss can at least partially be explained by the accumulation of higher molecular weight ubiquitinated forms of ErbB2 that are detectable with an extracellular but not intracellular domain directed antibody. We propose that POH1 may deubiquitinate ErbB2 and that this activity is not necessarily coupled to proteasomal degradation.
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