D-Type Cyclins and Gene Transcription

Abstract

D-type cyclins contribute the regulatory subunits to the holoenzymes that phosphorylate distinct substrates and regulate diverse biological processes, including cellular proliferation and differentiation. A growing body of evidence has demonstrated that the D-type cyclins are located in distinct subcellular pools with distinct functions. These subcellular locations include the cell membrane, the cytoplasm, the nuclear lamina, the nucleus, and DNA binding sites. The distribution of D-type cyclins in each one of these compartments is regulated by distinct signaling pathways and contributes to a vast array of biological processes. Importantly, D-type cyclins can also conduct transcriptional functions. Initially shown to regulate the activity of transcription factors in gene reporter assays, subsequent studies have shown that D-type cyclins can affect gene expression through the regulation of coactivators, the modulation of transcription factor binding in the context of chromatin, and their ability to serve as molecular scaffolds that facilitate the interactions between chromatin-modifying enzymes (histone and DNA methylases [Suv39, HP1α, G9a, DNMT1, PRMT1], histone acetylases [SRC1, p300, P/CAF], and histone deacetylases [HDAC1,3]). Genome-wide studies have shown that cyclin D1 associates with the regulatory regions of more than 2840 genes. The importance of the transcriptional functions of D-type cyclins has been demonstrated in vivo, as hormone signaling in prostate and mammary gland tissues is critically dependent upon the presence of cyclin D1. Furthermore, it is the cyclin D1-regulated gene expression signature, not the abundance of the protein, which strongly predicts poor outcome in prostate cancer. Together, these findings are consistent with the evolving realization that the D-type cyclins play an important biological role in governing gene transcription.