Cyclin D1 is a key regulator of cell proliferation as it links the extracellular signaling environment to cell cycle progression. Cyclin D1 accumulation is the rate-limiting step for cell cycle entry and the transition from G1 to S phase. The levels of cyclin D1 are elevated in G1 phase, where it interacts with the serine-threonine protein kinases, cyclin-dependent kinases (CDK) CDK4 and/or CDK6 to activate its catalytic activity. Active Cyclin D1/CDK complexes then phosphorylate the retinoblastoma protein (Rb). Rb inhibits cell cycle progression through its ability to repress E2F transcription factors activity, which is involved in the regulation of genes required for DNA replication and G2/M progression. Phosphorylation of RB (pRb) promotes the release of E2F and subsequently promotes cell cycle progression. Furthermore, cyclin D1 plays a role in maintaining the integrity of the G1/S checkpoint. Cyclin D1 associates with proliferating cell nuclear antigen (PCNA), a component of the DNA replication and repair machinery. During S phase, cyclin D1 down-regulation is necessary for PCNA translocation, DNA repair and initiation of DNA replication.
Cyclin D1 has been shown to associate with a number of transcription factors, HATs and HDACs in a CDK independent manner to modulate transcription and epigenetic changes. Cyclin D1 contains an LxxLL motif (251-255) that facilitates coactivator recruitment to mediate transcriptional activation. In addition, cyclin D1 contains a repressor domain (142-253) within its central region, which facilitates the interactions with corepressors to negatively regulate transcription. The levels of cyclin D1 are determined by the rate of expression, protein stability, localization, associations and degradation. The phosphorylation of cyclin D1 at Thr286 has been shown to target it for nuclear export and ubiquitin-proteasome degradation. The diverse roles of cyclin D1 are dependent on its protein level. The various biological processes that cyclin D1 has been implicated in include cell migration, mitochondrial metabolism, cell cycle arrest and apoptosis.
Given the pivotal role of cyclin D1 in promoting cell proliferation, aberrant cyclin D1 expression and activity frequently occurs in human cancers. The overexpression of cyclin D1 is predominantly associated with tumorigenesis and metastases. Understanding the multifaceted role of cyclin D1 and its dysregulation may provide a better understanding of its involvement in the development and progression of cancer.