Abstract
Original language | English |
---|---|
Journal | PLoS One |
Volume | 7 |
Issue number | 11 |
DOIs | |
Publication status | Published - Nov 2012 |
Externally published | Yes |
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
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In: PLoS One, Vol. 7, No. 11, 11.2012.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Modeling Truncated AR Expression in a Natural Androgen Responsive Environment and Identification of RHOB as a Direct Transcriptional Target
AU - Tsai, H.-C.
AU - Boucher, D.L.
AU - Martinez, A.
AU - Tepper, C.G.
AU - Kung, H.-J.
N1 - 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: [email protected] 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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RhoA, RhoB, RhoC, and cell motility (2004) Exp Cell Res, 301, pp. 43-49; Prendergast, G.C., Actin' up: RhoB in cancer and apoptosis (2001) Nat Rev Cancer, 1, pp. 162-168; Chen, C.D., Welsbie, D.S., Tran, C., Baek, S.H., Chen, R., Molecular determinants of resistance to antiandrogen therapy (2004) Nat Med, 10, pp. 33-39; Tararova, N.D., Narizhneva, N., Krivokrisenko, V., Gudkov, A.V., Gurova, K.V., Prostate cancer cells tolerate a narrow range of androgen receptor expression and activity (2007) Prostate, 67, pp. 1801-1815; Ceraline, J., Cruchant, M.D., Erdmann, E., Erbs, P., Kurtz, J.E., Constitutive activation of the androgen receptor by a point mutation in the hinge region: a new mechanism for androgen-independent growth in prostate cancer (2004) Int J Cancer, 108, pp. 152-157; Burnstein, K.L., Regulation of androgen receptor levels: implications for prostate cancer progression and therapy (2005) J Cell Biochem, 95, pp. 657-669; Wolf, D.A., Herzinger, T., Hermeking, H., Blaschke, D., Horz, W., Transcriptional and posttranscriptional regulation of human androgen receptor expression by androgen (1993) Mol Endocrinol, 7, pp. 924-936; Blok, L.J., Themmen, A.P., Peters, A.H., Trapman, J., Baarends, W.M., Transcriptional regulation of androgen receptor gene expression in Sertoli cells and other cell types (1992) Mol Cell Endocrinol, 88, pp. 153-164; Grad, J.M., Dai, J.L., Wu, S., Burnstein, K.L., Multiple androgen response elements and a Myc consensus site in the androgen receptor (AR) coding region are involved in androgen-mediated up-regulation of AR messenger RNA (1999) Mol Endocrinol, 13, pp. 1896-1911; Kumar, M.V., Jones, E.A., Grossmann, M.E., Blexrud, M.D., Tindall, D.J., Identification and characterization of a suppressor element in the 5′-flanking region of the mouse androgen receptor gene (1994) Nucleic Acids Res, 22, pp. 3693-3698; Wang, L.G., Ossowski, L., Ferrari, A.C., Androgen receptor level controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line (2004) Oncogene, 23, pp. 5175-5184; Cai, C., He, H.H., Chen, S., Coleman, I., Wang, H., Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1 (2011) Cancer Cell, 20, pp. 457-471; Ding, X.F., Anderson, C.M., Ma, H., Hong, H., Uht, R.M., Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities (1998) Mol Endocrinol, 12, pp. 302-313; Jenster, G., van der Korput, H.A., Trapman, J., Brinkmann, A.O., Identification of two transcription activation units in the N-terminal domain of the human androgen receptor (1995) J Biol Chem, 270, pp. 7341-7346; Hu, R., Lu, C., Mostaghel, E.A., Yegnasubramanian, S., Gurel, M., Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer (2012) Cancer Res, 72, pp. 3457-3462; Bourboulia, D., Stetler-Stevenson, W.G., Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion (2010) Semin Cancer Biol; Karlsson, R., Pedersen, E.D., Wang, Z., Brakebusch, C., Rho GTPase function in tumorigenesis (2009) Biochim Biophys Acta, 1796, pp. 91-98; Mazieres, J., Antonia, T., Daste, G., Muro-Cacho, C., Berchery, D., Loss of RhoB expression in human lung cancer progression (2004) Clin Cancer Res, 10, pp. 2742-2750; Bousquet, E., Mazieres, J., Privat, M., Rizzati, V., Casanova, A., Loss of RhoB expression promotes migration and invasion of human bronchial cells via activation of AKT1 (2009) Cancer Res, 69, pp. 6092-6099; Fritz, G., Brachetti, C., Bahlmann, F., Schmidt, M., Kaina, B., Rho GTPases in human breast tumours: expression and mutation analyses and correlation with clinical parameters (2002) Br J Cancer, 87, pp. 635-644; Vasilaki, E., Papadimitriou, E., Tajadura, V., Ridley, A.J., Stournaras, C., Transcriptional regulation of the small GTPase RhoB gene by TGF{beta}-induced signaling pathways (2010) FASEB J, 24, pp. 891-905; Yoneda, M., Hirokawa, Y.S., Ohashi, A., Uchida, K., Kami, D., RhoB enhances migration and MMP1 expression of prostate cancer DU145 (2010) Exp Mol Pathol, 88, pp. 90-95
PY - 2012/11
Y1 - 2012/11
N2 - 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. © 2012 Tsai et al.
AB - 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. © 2012 Tsai et al.
KW - androgen receptor
KW - doxycycline
KW - heterodimer
KW - messenger RNA
KW - article
KW - biological model
KW - carboxy terminal sequence
KW - cell migration
KW - cell shape
KW - cell strain LNCaP
KW - controlled study
KW - gene
KW - gene activation
KW - gene identification
KW - gene silencing
KW - gene targeting
KW - genetic transcription
KW - protein expression
KW - protein function
KW - protein localization
KW - receptor down regulation
KW - reverse transcription polymerase chain reaction
KW - RHOB gene
KW - transcription regulation
KW - upregulation
KW - Androgens
KW - Cell Line, Tumor
KW - Cell Movement
KW - Cell Nucleus
KW - Chromatin
KW - Dihydrotestosterone
KW - Doxycycline
KW - Gene Expression Regulation, Neoplastic
KW - Gene Knockdown Techniques
KW - Humans
KW - Male
KW - Prostatic Neoplasms
KW - Protein Binding
KW - Protein Multimerization
KW - Protein Transport
KW - Receptors, Androgen
KW - Reproducibility of Results
KW - Response Elements
KW - rhoB GTP-Binding Protein
KW - RNA, Messenger
KW - Transcription, Genetic
U2 - 10.1371/journal.pone.0049887
DO - 10.1371/journal.pone.0049887
M3 - Article
SN - 1932-6203
VL - 7
JO - PLoS One
JF - PLoS One
IS - 11
ER -