Cyclin D1 goes metabolic: dual functions of cyclin D1 in regulating lipogenesis.

Recent findings have revolutionized thinking in terms of how D-type cyclins control diverse cellular processes including development, cellular proliferation and carcinogenesis. The D-cyclin consists of three members with overlapping functions, cyclin D1, cyclin D2 and cyclin D3.1 Biochemically, D-type cyclins function in late G1 phase as catalysts for cyclin-dependent kinases 4 and/or 6 (CDK4/6). D-type cyclin production is generally enhanced by mitogenic stimuli, and enrichment of the D-cyclins initiates the cell cycle engine. Binding of cyclin D1 to CDK4/6 induces kinase activity and promotes cell cycle progression through phosphorylation of the retinoblastoma tumor suppressor protein, RB, thereby suppressing the ability of RB to attenuate cell cycle advancement. As such, elevated cyclin D1 expression in model systems drives unchecked cellular proliferation and promoting tumor growth.2 High levels of cyclin D1 are in fact associated with numerous human malignancies, including both breast cancer and hepatocellular carcinoma. Moreover, a variant of cyclin D1 that arises from alternative splicing of the CCND1 transcript, gives rise to a highly oncogenic form of the protein (cyclin D1b), which is associated with aggressive tumor phenotypes.3 Given the importance of D-cyclins in controlling the phenotypes associated with human cancers, this aspect of cyclin D function has been widely studied and is well understood. While the pro-proliferative actions of cyclin D1 are largely mediated by CDKs, it is clear that the D-cyclins harbor a number of critical, CDK-independent functions. Strikingly, unbiased biochemical analysis revealed that a major fraction of endogenous cyclin D1 is found in association with transcription factors.4 Subsequent analyses demonstrated that cyclin D1 is found at promoters and is a key mediator of selected transcription factor functions. The ability of cyclin D1 to regulate transcription appears to underpin major in vivo activity; exemplifying this, the retinal hypoplastic phenotype of the cyclin D1-knockout mouse results from loss of cyclin D1-mediated Notch signaling. The finding that cyclin D1-controlled transcriptional regulation controls in vivo phenotypes is consistent with a litany of previous studies identifying cyclin D1 as a regulator of nuclear receptors. Cyclin D1 associates with and modulates function of the androgen receptor (AR),5 estrogen receptor alpha (ER),6 PPAR-gamma,7 thyroid hormone receptor beta (TR-B) and multiple nuclear receptor co-regulators. Morever, cyclin D1 can regulate androgen and estrogen metabolism in the liver, further implicating the protein as a major effector of hormone action.8 In a new study by Hanse and colleagues,9 cyclin D1 was identified as a critical mediator of de novo hepatic lipogenesis, manifest by both CDK-dependent and CDK-independent mechanisms. Initial studies demonstrated that cyclin D1 inhibits lipogenesis in primary rat hepatocytes, and was associated with altered lipogenic gene expression programs that are distinct from the role of cyclin D1 in facilitating injury-induced hepatocyte proliferation. The underlying mechanisms hinge upon two distinct actions of cyclin D1. First, cyclin D1 negatively regulates ChREBP (carbohydrates response element-binding protein) expression and activity in a manner dependent on CDK4 function. The ChREBP transcription factor is typically activated by high glucose and promotes expression of genes whose functions are important for mediating hepatic lipogenesis. By contrast, cyclin D1 binds to and suppress the function of HNF4α (Hepatocyte nuclear factor 4 alpha), a member of the nuclear receptor superfamily that influences liver function. Cyclin D1 suppresses binding of HNF4α to chromatin at regulatory regions of target genes associated with lipogenesis, and the impact of cyclin D1 was further confirmed by the observation that cyclin D1 knockdown enhanced both HNF4α activity and lipogenesis. Finally, the relationship between liver regeneration and the lipogenic response was examined with a focus on cyclin D1 activity; as expected, injury introduced by partial hepatectomy induced cyclin D1 expression and hepatocyte cell cycle advancement. Notably, injury-induced cellular proliferation was associated with a concomitant suppression of lipogenic gene expression. Combined, these findings suggest that altered metabolic function during liver regeneration may be attributed to more than alteration of hepatic mass, but may be controlled by the induction of cyclin D1-mediated transcription regulation. As the study establishes a new link between cell cycle regulation and hepatic metabolism, the implications of these cyclin D1 functions for liver development, homeostasis and cancer should be explored. On balance, these studies provide further impetus for discerning the cellular and biological impact of cyclin D1-mediated transcriptional regulation.9