A central domain of cyclin D1 mediates nuclear receptor corepressor activity

Abstract

Regulation of nuclear receptor activity is the focus of numerous ongoing studies to develop novel therapies for the treatment of hormone-related cancer. Although cyclin D1 functions to control the activity of several nuclear receptors, the region(s) of the protein responsible for such transcriptional comodulation remain poorly defined. Herein, we map the region of cyclin D1 required for binding and repression of the androgen receptor (AR) to a central, exclusively a-helical domain. Deletion of this domain disrupted AR binding and corepressor activity. Further investigations showed that this domain is sufficient for AR interaction and possesses the ability to bind histone deacetylase 3. Strikingly, overexpression of this repressor region attenuates cell cycle progression in prostatic adenocarcinoma cells. The requirement of this domain for nuclear receptor repression was conserved with respect to thyroid hormone receptor beta-1, whereas cyclin D1 activation of the estrogen receptor occurred independently of the central region. Together, these data identify a minimal repression module within cyclin D1 and demonstrate that the coactivator and corepressor functions of cyclin D1 are distinct. In addition, our data suggest that properties of the cyclin D1 central domain could be exploited to develop novel prostate cancer therapeutics.

Impact of differential cyclin D1 expression and localisation in prostate cancer

“…It has been previously shown through in vitro studies that cyclin D1 can influence androgen-dependent prostate cancer cell proliferation through its dual ability to modulate both CDK4 and AR activity (Petre-Draviam et al, 2005;Burd et al, 2006a). To elucidate further the role of cyclin D1 in prostate cancer, primary human prostate cancer specimens were utilised to assess the influence of cyclin D1 expression and localisation on PSA levels and proliferation index.…”

“…First, cyclin D1 binds an N-terminal region of AR that is required for docking to its C terminus upon ligand binding and suppresses the efficacy of this N -C interaction . Second, cyclin D1 can associate with histone deacetylases to repress transcription, and this function of cyclin D1 is essential for its AR corepressor activity Petre-Draviam et al, 2005). Cyclin D1 can also bind to and modulate other transcription factors by similar mechanisms, with the largest class of proteins belonging to the nuclear receptor superfamily (Coqueret, 2002;Ewen and Lamb, 2004;Fu et al, 2004).…”

Cyclin D1: polymorphism, aberrant splicing and cancer risk

“…Each of these activities have been mapped to specific regions of the cyclin D1 protein. Specifically, transcriptional activation is associated with an LxxLL motif that is important for coactivator recruitment (Zwijsen et al, 1998;McMahon et al, 1999), whereas transcriptional repression is associated with the presence of a repressor domain for selected transcription factors (Petre-Draviam et al, 2005). The biological significance of the cyclin D1 transcriptional regulatory function was solidified in a large scale, comprehensive analysis of genes deregulated in breast cancer specimens (Lamb et al, 2003).…”

Cyclin D3 action in androgen receptor regulation and prostate cancer

“…For cyclin D1, these activities were mapped to a central repressor domain that is sufficient for AR binding and modulation (Petre-Draviam et al, 2005). Sequence alignment and secondary structure analyses revealed a putative conservation of the repressor domain (RD3) within cyclin D3 (Supplementary Figure S4).…”

“…Mechanisms are attributed to a discrete repressor domain, which binds to the AR N-terminus and prevents ligand-dependent conformational changes in AR . Additionally, this motif can recruit histone deacetylase 3 (HDAC3), and the AR-repressor function of cyclin D1 is dependent on HDAC function (Lin et al, 2002;Petre et al, 2002;Petre-Draviam et al, 2005). Concordantly, the repressor domain of cyclin D1 is also required for cyclin D1-mediated suppression of peroxisome proliferator-activated receptor-g activity (Fu et al, 2005).…”