Article

Coactivator selective regulation of androgen receptor activity.

Department of Molecular and Cellular Biology, Baylor College of Medicine, M130, One Baylor Plaza, Houston, TX 77030, United States.
Steroids (impact factor: 2.83). 09/2009; 74(8):669-74. DOI:10.1016/j.steroids.2009.02.007
Source: PubMed

ABSTRACT The androgen receptor (AR) is a ligand activated nuclear receptor, which regulates transcription and stimulates growth of androgen dependent prostate cancer. To regulate transcription, AR recruits a series of coactivators that modify chromatin and facilitate transcription. However, information on ligand and target gene-specific requirements for coactivators is limited. We compared the actions of the p160 coactivators SRC-1 and SRC-3/RAC3 with SRA (steroid receptor RNA activator). All three coactivate AR in the presence of agonist as expected. However, overexpression of either SRC-1 or SRC-3 increased AR activity in response to the partial antagonist, cyproterone acetate, whereas SRA was unable to stimulate AR activity under these conditions. Using siRNA to reduce expression of these coactivators in LNCaP cells, we also found promoter specific requirement for these coactivators. SRC-3 is required for optimal androgen dependent induction of PSA, TMPRSS2, and PMEPA1 whereas SRA is required only for optimal induction of the TMPRSS2 gene. These data indicate that different groups of AR target genes have distinct requirements for coactivators and response to AR ligands.

0 0
 · 
0 Bookmarks
 · 
36 Views
  • Article: SLIRP, a small SRA binding protein, is a nuclear receptor corepressor.
    Esme C Hatchell, Shane M Colley, Dianne J Beveridge, Michael R Epis, Lisa M Stuart, Keith M Giles, Andrew D Redfern, Lauren E C Miles, Andrew Barker, Louisa M MacDonald, Peter G Arthur, James C K Lui, Jemma L Golding, Ross K McCulloch, Cecily B Metcalf, Jackie A Wilce, Matthew C J Wilce, Rainer B Lanz, Bert W O'Malley, Peter J Leedman
    [show abstract] [hide abstract]
    ABSTRACT: Steroid receptor RNA activator (SRA), the only known RNA coactivator, augments transactivation by nuclear receptors (NRs). We identified SLIRP (SRA stem-loop interacting RNA binding protein) binding to a functional substructure of SRA, STR7. SLIRP is expressed in normal and tumor tissues, contains an RNA recognition motif (RRM), represses NR transactivation in a SRA- and RRM-dependent manner, augments the effect of Tamoxifen, and modulates association of SRC-1 with SRA. SHARP, a RRM-containing corepressor, also binds STR7, augmenting repression with SLIRP. SLIRP colocalizes with SKIP (Chr14q24.3), another NR coregulator, and reduces SKIP-potentiated NR signaling. SLIRP is recruited to endogenous promoters (pS2 and metallothionein), the latter in a SRA-dependent manner, while NCoR promoter recruitment is dependent on SLIRP. The majority of the endogenous SLIRP resides in the mitochondria. Our data demonstrate that SLIRP modulates NR transactivation, suggest it may regulate mitochondrial function, and provide mechanistic insight into interactions between SRA, SLIRP, SRC-1, and NCoR.
    Molecular Cell 07/2006; 22(5):657-68. · 14.18 Impact Factor
  • Article: Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression.
    Irina U Agoulnik, Ajula Vaid, William E Bingman, Halime Erdeme, Anna Frolov, Carolyn L Smith, Gustavo Ayala, Michael M Ittmann, Nancy L Weigel
    [show abstract] [hide abstract]
    ABSTRACT: Prostate cancer is initially androgen dependent and there is evidence that androgen receptor continues to play a role in androgen-independent prostate cancer. Androgen receptor activity depends both on the level of androgens and on the level of coactivators that interact with androgen receptor. Our goal was to evaluate the role of the androgen receptor coactivator SRC-1 in prostate cancer progression. Using tissue arrays to measure SRC-1 protein levels, we found that increased SRC-1 expression in clinically localized, androgen-dependent cancer is associated with clinical and pathologic variables of increased tumor aggressiveness. Interestingly, there was variable expression of SRC-1 in normal prostate tissue which correlated with the staining intensity of the corresponding cancer tissue. To test the contribution of SRC-1, we examined its role in androgen-dependent LNCaP and androgen-independent C4-2 prostate cancer cell lines. Using small interfering RNA to reduce expression of androgen receptor, we found that androgen receptor was required both for cell growth and for basal expression of prostate-specific antigen in the androgen-independent C4-2 cell line. Thus, although the cells can grow in an androgen-depleted medium, they remained androgen receptor dependent. Reduction of SRC-1 expression significantly reduced growth and altered androgen receptor target gene regulation in both LNCaP and C4-2 cell lines whereas it had no effect on the growth of the androgen receptor-negative PC-3 and DU145 prostate cancer cell lines. Although the requirement for androgens and androgen receptor in the development of prostate cancer is well established, our study implicates enhanced androgen receptor activity through elevated expression of SRC-1 in the development of more aggressive disease in men with prostate cancer.
    Cancer Research 10/2005; 65(17):7959-67. · 7.86 Impact Factor
  • Article: SRC-3 is required for prostate cancer cell proliferation and survival.
    Hai-Jun Zhou, Jun Yan, Weiping Luo, Gustavo Ayala, Sue-Hwa Lin, Halime Erdem, Michael Ittmann, Sophia Y Tsai, Ming-Jer Tsai
    [show abstract] [hide abstract]
    ABSTRACT: Prostate cancer is the most common cancer in men in America. Currently, steroid receptor coactivators have been proposed to mediate the development and progression of prostate cancer, at times in a steroid-independent manner. Steroid receptor coactivator-3 (SRC-3, p/CIP, AIB1, ACTR, RAC3, and TRAM-1) is a member of the p160 family of coactivators for nuclear hormone receptors including the androgen receptor. SRC-3 is frequently amplified or overexpressed in a number of cancers. However, the role of SRC-3 in cancer cell proliferation and survival is still poorly understood. In this study, we show that SRC-3 is overexpressed in prostate cancer patients and its overexpression correlates with prostate cancer proliferation and is inversely correlated with apoptosis. Consistent with patient data, we have observed that reduction of SRC-3 expression by small interfering RNA decreases proliferation, delays the G1-S transition, and increases cell apoptosis of different prostate cancer cell lines. Furthermore, with decreased SRC-3 expression, proliferating cell nuclear antigen and Bcl-2 expression, as well as bromodeoxyuridine incorporation in prostate cancer cells are reduced. Finally, knockdown of SRC-3 with inducible short hairpin RNA expression in prostate cancer cells decreased tumor growth in nude mice. Taken together, these findings indicate that SRC-3 is an important regulator of prostate cancer proliferation and survival.
    Cancer Research 10/2005; 65(17):7976-83. · 7.86 Impact Factor

Show more

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

AR activity
 
AR ligands
 
AR target genes
 
cyproterone acetate
 
different groups
 
ligand activated nuclear receptor
 
LNCaP cells
 
modify chromatin
 
optimal androgen dependent induction
 
optimal induction
 
p160 coactivators SRC-1
 
partial antagonist
 
promoter specific requirement
 
regulates transcription
 
steroid receptor RNA activator
 
stimulate AR activity
 
stimulates growth
 
target gene-specific requirements
 
three coactivate AR
 
TMPRSS2 gene