A 6-kb Promoter Fragment Mimics in Transgenic Mice the Prostate-Specific and Androgen-Regulated Expression of the Endogenous Prostate-Specific Antigen Gene in Humans

Cleutjens, Kitty B.J.M.; Korput, Hetty A. G. M. van der; Eekelen, Conny C. Ehren-van; Sikes, Robert A.; Fasciana, Claudia; Chung, Leland W.K.; Trapman, Jan

doi:10.1210/mend.11.9.9974

Cited by 92 publications

(25 citation statements)

References 39 publications

(70 reference statements)

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“…To further understand the molecular underpinnings of hormone induction of gene expression, we analyzed androgen-induced recruitment of AR and its associated coactivators to the entire 5Ј regulatory region of the prostate-specific antigen (PSA) gene in hormoneresponsive LNCaP cells. High-level androgen induction of PSA expression is conferred by an enhancer centered at ϷϪ4.2 kb on the PSA gene, which contains multiple tandem androgen response elements (18)(19)(20). Here, we show that on androgen stimulation, the p160 and CBP͞p300 coactivators are preferentially recruited to the enhancer.…”

mentioning

confidence: 68%

Androgen-induced recruitment of RNA polymerase II to a nuclear receptor–p160 coactivator complex

Louie

Yang

Hong

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

141

116

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The androgen receptor, like other nuclear receptors, activates target genes by binding to hormone-responsive enhancers. Here we demonstrate that androgen induces robust recruitment of androgen receptor, members of the p160 coactivator family, and CREB-binding protein͞p300 specifically at the distant enhancer of prostate-specific antigen (PSA) gene. Unexpectedly, we found that RNA polymerase II (Pol II) is directly recruited to the enhancer in a hormone-dependent manner, independent of the proximal promoter, and that the isolated PSA enhancer can mediate efficient androgen induction of transcription. Inhibition of the Pol II carboxyl-terminal domain kinase activity with low concentrations of flavopiridol blocks Pol II transfer from the enhancer to the promoter and selectively abolishes PSA induction by androgen. Moreover, elevated levels of the p160 coactivator ACTR͞ AIB1 increase both androgen-dependent and -independent PSA expression, by facilitating Pol II recruitment to the enhancer. These results support a model in which nuclear receptors and their coactivators mediate hormone induction by serving as a staging platform for Pol II recruitment.A ndrogen is a key regulator of cell growth and differentiation in male sexual development and function as well as in the progression of prostate cancer. These hormonal effects are mediated by the androgen receptor (AR), a member of the nuclear receptor superfamily, which consists of liganddependent transcription factors (1). Recently, a growing number of nuclear proteins have been found to associate with AR and are postulated to mediate transcriptional control by the receptor (2, 3). Among them are members of the p160 coactivator family, including SRC-1, TIF2͞GRIP1, and ACTR (AIB1͞RAC3͞ TRAM1͞pCIP). The p160 coactivators associate with nuclear receptors in a hormone-dependent fashion primarily through the central receptor-interaction domain that harbors several LXXLL motifs.Although p160 coactivators possess intrinsic histone acetylase (HAT) activities, they are also capable of recruiting other HAT proteins such as CREB-binding protein (CBP), p300, and PCAF (4, 5), and the nuclear protein arginine methyltransferases CARM1 and PRMT (6, 7). Both the acetylases and methylases can regulate transcription by modifying nucleosomal and nonnucleosomal nuclear proteins (7,8). However, how the p160 coactivators promote RNA polymerase II (Pol II) transcription is still not well understood. Domain mapping experiments suggest that transactivation by the p160 coactivators is largely attributable to their recruitment of CBP͞p300 and the HAT activities (4, 9-12). Although earlier experiments indicate that CBP͞p300 may interact directly with the Pol II complex (13,14), this notion lost currency with the discovery of the importance of the HAT activity in transcriptional activation and the more recent demonstration that the simple recruitment and assembly of Pol II machinery in mammalian cells is not sufficient for productive transcription (15, 16).Previously, we and others demonstrated th...

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mentioning

confidence: 68%

Androgen-induced recruitment of RNA polymerase II to a nuclear receptor–p160 coactivator complex

Louie

Yang

Hong

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

141

116

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“…Several of the promoters described above such as rat probasin or mouse C3/PSBP for epithelial cells and cryptdin for neuroendocrine cells will be particularly useful in this regard. In addition, other promoters are emerging for this purpose, including human PSA (Cleutjens et al, 1997;Wei et al, 1997Wei et al, , 1998Willis et al, 1998). Access to candidate genes will be facilitated greatly by human genome mapping, the Cancer Genome Anatomy Project (CGAP), and microarray technology, as well as by gene discovery e orts in chromosomal regions of recurrent prostatetumor associated loss or gain.…”

Section: Future Directionsmentioning

confidence: 99%

Mouse models of prostate cancer

Sharma

Schreiber‐Agus

1999

Oncogene

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“…Recently, our ability to assess the impact of individual gene products in the prostate has been greatly facilitated by the characterization of gene promoters that enable targetting to the prostate (Greenberg et al, 1994;Maroulakou et al, 1994;Pang et al, 1997;Cleutjens et al, 1997;Zhang et al, 1997). The most extensively studied transgenic model involves the targeting of transgene expression using the probasin promoter (Greenberg et al, 1995;Gingrich et al, 1996Gingrich et al, , 1997.…”

Section: Introductionmentioning

confidence: 99%

The impact of bcl-2 expression and bax deficiency on prostate homeostasis in vivo

et al. 2000

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Prostatic glandular epithelial cells undergo apoptosis in response to androgen-deprivation. The molecular determinants of androgen-responsiveness in these cells are incompletely understood. Recent evidence suggests that bcl-2 gene family members may be important in this context. We used the probasin promoter to target a human bcl-2 transgene speci®cally to the prostate in order to assess its impact on conferring resistance to androgen withdrawal in, otherwise sensitive, prostatic glandular epithelial cells in vivo. We examined the contribution of bax to mediating androgen-responsiveness in prostatic glandular epithelial cells using bax knockout mice. The histologic appearance of the prostates from probasin-bcl-2 transgenic mice or bax 7/7 mice did not di er from those of control littermates. There was no evidence of hyperplastic or neoplastic growth. There was no di erence between probasin bcl-2 transgenic mice, bax 7/7 mice, and control littermates in steady-state levels of apoptosis. Following castration our ®ndings suggest that both bax and bcl-2 may each contribute to the androgen-responsiveness of prostatic glandular epithelial cells. It is apparent from these results, however, that bax is not required to mediate cell death in prostatic glandular epithelial cells following castration. A comparison between the apoptotic indices in the ventral prostate from the probasin-bcl-2 and bax 7/7 mice following castration suggests that the presence of bcl-2 may be a more important indicator of androgensensitivity than a de®ciency of bax.

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A 6-kb Promoter Fragment Mimics in Transgenic Mice the Prostate-Specific and Androgen-Regulated Expression of the Endogenous Prostate-Specific Antigen Gene in Humans

Cited by 92 publications

References 39 publications

Androgen-induced recruitment of RNA polymerase II to a nuclear receptor–p160 coactivator complex

Androgen-induced recruitment of RNA polymerase II to a nuclear receptor–p160 coactivator complex

Mouse models of prostate cancer

The impact of bcl-2 expression and bax deficiency on prostate homeostasis in vivo

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