Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer

Abstract

Regulation of the androgen receptor (AR) is critical to prostate cancer (PCa) development; therefore, AR is the first line therapeutic target for disseminated tumors. Cell cycle dependent accumulation of cyclin D1 negatively modulates the transcriptional regulation of the AR through discrete, CDK4-independent mechanisms. The transcriptional co-repressor function of cyclin D1 resides within a defined motif termed ther repressor domain (RD), and it was hypothesized that this motif could be utilized as a platform to develop new strategies for blocking AR function. Here, we demonstrate that expression of the RD peptide is sufficient to disrupt AR transcriptional activation of multiple, prostate-specific AR target genes. Importantly, these actions are sufficient to specifically inhibit S-phase progression in AR-positive PCa cells, but not in AR-negative cells or tested AR-positive cells of other lineages. As expected, impaired cell cycle progression resulted in a suppression of cell doubling. Additionally, cell death was observed in AR-positive cells that maintain androgen dependence and in a subset of castrate-resistant PCa cells, dependent on Akt activation status. Lastly, the ability of RD to cooperate with existing hormone therapies was examined, which revealed that RD enhanced the cellular response to an AR antagonist. Together, these data demonstrate that RD is sufficient to disrupt AR-dependent transcriptional and proliferative responses in PCa, and can enhance efficacy of AR antagonists, thus establishing the impetus for development of RD-based mimetics.

Cyclin D1 Is a Selective Modifier of Androgen-dependent Signaling and Androgen Receptor Function

“…The prostate is a unique model to study the transcriptional consequence of cyclin D1 because androgens are important for the growth and survival of PCa cells. The mechanisms by which cyclin D1 elicits transcriptional repression have been preliminarily characterized (23,30,32,34,36), and the clinical importance has been suggested because human PCa specimens that lack cyclin D1 are associated with elevated serum PSA (27). The current study was conducted using physiological concentrations of androgen, and the number of overall androgen-regulated transcripts identified is consistent with previous reports (78 -81).…”

“…Thus, the ability of cyclin D1 to suppress AR activity appears to be diminished in PCa, consistent with the role of AR in promoting tumor development and progression (35). Conversely, introduction of the isolated cyclin D1 domain (repressor domain) responsible for transcriptional regulation of AR revealed that this functional motif is sufficient to attenuate ligand-dependent AR activity, cooperate with AR-directed therapeutics, and reduce cell viability in AR-dependent PCa cells (36). Combined, these findings identify cyclin D1 as a major effector of AR function and cellular outcomes in PCa.…”

Cyclin D1 Inhibits Mitochondrial Activity in B Cells

“…However, the central domain (142-253 aa), which is necessary for interactions with transcription factors or nuclear receptors (34)(35)(36), is required for this activity. Cyclin D1 is located at the OMM, where it binds VDAC through its central domain.…”

Cyclin D2 is a GATA4 cofactor in cardiogenesis

“…In addition to the Rb protein family, cyclin D-CDK4 complex was found to phosphorylate other transcription factors involved in cell proliferation/arrest, such as the transcription factor SMAD3 and the myb like transcription factor, DMP1 (3,4). Moreover, Cyclin Ds have been shown to interact with transcription coactivators/corepressors such as CBP, p300, P/CAF and HDACs (5)(6)(7)(8) and a repressor domain distinct from the CDK regulatory domain has been identified on CycD1 (9). As such, Cyclin Ds play important roles as CDKdependent and -independent transcriptional modulators.…”