novel-method-plasmid-dna-delivery-to-mouse-bladder-urothelium

Novel Method of Plasmid DNA Delivery to Mouse Bladder Urothelium by Electroporation

Genetically engineered mouse models (GEMMs) are extremely valuable in revealing novel biological insights into the initiation and progression mechanisms ...

University of California, Santa Cruz

NK3 homeobox 1 (Nkx3.1), a transcription factor expressed in the prostate epithelium, is crucial for maintaining prostate cell fate and suppressing tumor initiation. Nkx3.1 is ubiquitously expressed in luminal cells of hormonally intact prostate but, upon androgen deprivation, exclusively labels a type of luminal stem cells named castration-resistant Nkx3.1-expressing cells (CARNs). During prostate cancer initiation, Nkx3.1 expression is frequently lost in both humans and mouse models. Therefore, investigating how Nkx3.1 expression is regulated  is important for understanding the mechanisms of prostate stem cell specification and cancer initiation. Here, using a transgenic mouse line with destabilized GFP, we identified an 11-kb genomic region 3' of the  transcription start site to be responsible for alterations in Nkx3.1 expression patterns under various physiological conditions. We found that androgen cell-autonomously activates Nkx3.1 expression through androgen receptor (AR) binding to the 11-kb region in both normal luminal cells and CARNs and discovered new androgen response elements in the  3' UTR. In contrast, we found that, in  prostate tumors, loss of Nkx3.1 expression is mediated at the transcriptional level through the 11-kb region despite functional AR in the nucleus. Importantly, the GFP reporter specifically labeled CARNs in the regressed prostate only in the presence of cell-autonomous AR, supporting a facultative model for CARN specification.

Zhu A. Wang

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JoVE Journal Publications

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