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Pro statu isto translation1/25/2024 While the role of the AR signaling axis in transcriptional regulation is well documented, very little is known regarding its role in translation initiation proposed in early studies. Importantly, recent results indicate that the function of the AR is specific to the disease stage, triggering a different gene expression program in androgen-dependent as compared to androgen-independent prostate cancer. Clinical and experimental evidence suggest that prostate cancer progression occurs through alteration of the normal androgen signaling, reducing the specificity or the amount of AR ligand required for proliferation and survival. Binding of androgens to the AR promotes a conformational change that ultimately leads to its translocation to the nucleus and regulation of transcription of a specific set of androgen-responsive genes. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interest exist.Īndrogens signaling through the AR play an essential role in normal prostate development and contribute to the progression of prostate cancer. No additional external funding was received for this study. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work was supported in part by a grant from the National Cancer Institute (1R15CA155873). Received: JAccepted: DecemPublished: February 6, 2013Ĭopyright: © 2013 Overcash et al. University of Colorado, United States of America These results indicate that androgen signaling promotes eIF2α phosphorylation and subsequent translation of TMEFF2 via a mechanism that requires uORFs in the 5′-UTR of TMEFF2.Ĭitation: Overcash RF, Chappell VA, Green T, Geyer CB, Asch AS, Ruiz-Echevarría MJ (2013) Androgen Signaling Promotes Translation of TMEFF2 in Prostate Cancer Cells via Phosphorylation of the α Subunit of the Translation Initiation Factor 2. Moreover, endoplasmic reticulum (ER) stress conditions, which promote eIF2α phosphorylation, also stimulate TMEFF2 translation. Importantly, DHT also promotes phosphorylation of the α subunit of the translation initiation factor 2 (eIF2α) in an AR-dependent manner, paralleling the effect on TMEFF2 translation. Using chemical and siRNA inhibition of the androgen receptor (AR), we show that the androgen effect on TMEFF2 translation is mediated by the AR. Addition of physiological concentrations of dihydrotestosterone (DHT) to prostate cancer cell lines increases translation of endogenous TMEFF2 or transfected TMEFF2-Luciferase fusions, and this effect requires the presence of upstream open reading frames (uORFs) in the 5′-untranslated region (5′-UTR) of TMEFF2. Here we show that translation of TMEFF2 is regulated by androgens. Although androgens promote tmeff2 transcription, androgen delivery to castrated animals carrying CWR22 xenografts increases TMEFF2 protein levels in the absence of mRNA changes, suggesting that TMEFF2 may also be post-transcriptionally regulated. Expression of TMEFF2 is deregulated in prostate cancer, suggesting a role in this disease, but the molecular mechanism(s) involved in this effect are not clear. The type I transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2), is expressed mainly in brain and prostate.
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