@article{c7cda1e7c1bc477fb5130b9c7e95b198,
title = "Modeling Truncated AR Expression in a Natural Androgen Responsive Environment and Identification of RHOB as a Direct Transcriptional Target",
abstract = "Recent studies identifying putative truncated androgen receptor isoforms with ligand-independent activity have shed new light on the acquisition of androgen depletion independent (ADI) growth of prostate cancer. In this study, we present a model system in which a C-terminally truncated variant of androgen receptor (TC-AR) is inducibly expressed in LNCaP, an androgen-dependent cell line, which expresses little truncated receptor. We observed that when TC-AR is overexpressed, the endogenous full length receptor (FL-AR) is transcriptionally downmodulated. This in essence allows us to {"}replace{"} FL-AR with TC-AR and compare their individual properties in exactly the same genetic and cellular background, which has not been performed before. We show that the TC-AR translocates to the nucleus, activates transcription of AR target genes in the absence of DHT and is sufficient to confer ADI growth to the normally androgen dependent LNCaP line. We also show that while there is significant overlap in the genes regulated by FL- and TC-AR there are also differences in the respective suites of target genes with each AR form regulating genes that the other does not. Among the genes uniquely activated by TC-AR is RHOB which is shown to be involved in the increased migration and morphological changes observed in LN/TC-AR, suggesting a role of RHOB in the regulation of androgen-independent behavior of prostate cancer cells. {\textcopyright} 2012 Tsai et al.",
keywords = "androgen receptor, doxycycline, heterodimer, messenger RNA, article, biological model, carboxy terminal sequence, cell migration, cell shape, cell strain LNCaP, controlled study, gene, gene activation, gene identification, gene silencing, gene targeting, genetic transcription, protein expression, protein function, protein localization, receptor down regulation, reverse transcription polymerase chain reaction, RHOB gene, transcription regulation, upregulation, Androgens, Cell Line, Tumor, Cell Movement, Cell Nucleus, Chromatin, Dihydrotestosterone, Doxycycline, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Male, Prostatic Neoplasms, Protein Binding, Protein Multimerization, Protein Transport, Receptors, Androgen, Reproducibility of Results, Response Elements, rhoB GTP-Binding Protein, RNA, Messenger, Transcription, Genetic",
author = "H.-C. Tsai and D.L. Boucher and A. Martinez and C.G. Tepper and H.-J. Kung",
note = "引用次數:9 Export Date: 5 March 2018 通訊地址: Kung, H.-J.; Department of Biochemistry and Molecular Medicine, School of Medicine and Cancer Center, University of California Davis, Davis, CA, United States; 電子郵件: hkung@ucdavis.edu 化學物質/CAS: doxycycline, 10592-13-9, 17086-28-1, 564-25-0, 94088-85-4; Androgens; Chromatin; Dihydrotestosterone, 521-18-6; Doxycycline, 564-25-0; RNA, Messenger; Receptors, Androgen; rhoB GTP-Binding Protein, 3.6.5.2 參考文獻: Tan, J., Sharief, Y., Hamil, K.G., Gregory, C.W., Zang, D.Y., Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells (1997) Mol Endocrinol, 11, pp. 450-459; Tepper, C.G., Boucher, D.L., Ryan, P.E., Ma, A.H., Xia, L., Characterization of a novel androgen receptor mutation in a relapsed CWR22 prostate cancer xenograft and cell line (2002) Cancer Res, 62, pp. 6606-6614; Chlenski, A., Nakashiro, K., Ketels, K.V., Korovaitseva, G.I., Oyasu, R., Androgen receptor expression in androgen-independent prostate cancer cell lines (2001) Prostate, 47, pp. 66-75; Li, Y., Alsagabi, M., Fan, D., Bova, G.S., Tewfik, A.H., Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression (2011) Cancer Res, 71, pp. 2108-2117; Libertini, S.J., Tepper, C.G., Rodriguez, V., Asmuth, D.M., Kung, H.J., Evidence for calpain-mediated androgen receptor cleavage as a mechanism for androgen independence (2007) Cancer Res, 67, pp. 9001-9005; Dehm, S.M., Schmidt, L.J., Heemers, H.V., Vessella, R.L., Tindall, D.J., Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance (2008) Cancer Res, 68, pp. 5469-5477; Hu, R., Dunn, T.A., Wei, S., Isharwal, S., Veltri, R.W., Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer (2009) Cancer Res, 69, pp. 16-22; Guo, Z., Yang, X., Sun, F., Jiang, R., Linn, D.E., A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth (2009) Cancer Res, 69, pp. 2305-2313; Hornberg, E., Ylitalo, E.B., Crnalic, S., Antti, H., Stattin, P., Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival (2011) PLoS One, 6, pp. e19059; Hu, R., Isaacs, W.B., Luo, J., A snapshot of the expression signature of androgen receptor splicing variants and their distinctive transcriptional activities (2011) Prostate, 71, pp. 1656-1667; Sun, S., Sprenger, C.C., Vessella, R.L., Haugk, K., Soriano, K., Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant (2010) J Clin Invest, 120, pp. 2715-2730; Guo, Z., Qiu, Y., A new trick of an old molecule: androgen receptor splice variants taking the stage?! 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year = "2012",
month = nov,
doi = "10.1371/journal.pone.0049887",
language = "English",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "11",
}
