Minireview: Cyclin D1: Normal and Abnormal Functions

Abstract

Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein and promotes progression through the G1-S phase of the cell cycle. Amplification or overexpression of cyclin D1 plays pivotal roles in the development of a subset of human cancers including parathyroid adenoma, breast cancer, colon cancer, lymphoma, melanoma, and prostate cancer. Of the three D-type cyclins, each of which binds cyclin-dependent kinase (CDK), it is cyclin D1 overexpression that is predominantly associated with human tumorigenesis and cellular metastases. In recent years accumulating evidence suggests that in addition to its original description as a CDK-dependent regulator of the cell cycle, cyclin D1 also conveys cell cycle or CDK-independent functions. Cyclin D1 associates with, and regulates activity of, transcription factors, coactivators and corepressors that govern histone acetylation and chromatin remodeling proteins. The recent findings that cyclin D1 regulates cellular metabolism, fat cell differentiation and cellular migration have refocused attention on novel functions of cyclin D1 and their possible role in tumorigenesis. In this review, both the classic and novel functions of cyclin D1 are discussed with emphasis on the CDK-independent functions of cyclin D1.

Cyclin D1 immunoreactivity in normal endocervix and diagnostic value in reactive and neoplastic endocervical lesions

“…Cyclin D1 also exhibits CDK-independent activities that influence apoptotic pathways, cellular migration, and angiogenesis all of which may be important in the neoplastic context. [10][11][12]16 Over-expression of cyclin D1 has been documented in diverse neoplasms including breast carcinoma, head and neck squamous carcinoma, parathyroid adenoma and mantle cell lymphoma, and some studies have shown a correlation between increased cyclin D1 and adverse prognosis. Therefore, our observation that cyclin D1 immunoreactivity was usually lost in neoplastic endocervical lesions seemed to be a counter-intuitive finding, particularly as such lesions are known to show prominent mitotic activity.…”

“…Many tumors exhibit abnormalities within the RB-p16-cyclin D1 pathways, and often these lead to increased activity of cyclin D1. [10][11][12] However, we have noted in routine practice that adenocarcinoma in situ and invasive cervical adenocarcinoma usually lack expression of cyclin D1, whereas the nuclei of most normal endocervical epithelial cells are positively stained. This seems a surprising finding as neoplastic endocervical lesions are typically characterized by prominent mitotic activity and show increased expression of the proliferationassociated marker Ki-67/MIB-1.…”

“…[10][11][12] Cyclin D1 associates with the cyclindependent kinases (CDKs), mainly CDK4 or CDK6, to form a complex that phosphorylates and hence inhibits the function of the retinoblastoma (RB) protein. In turn, loss of RB protein activity induces cells to enter S phase and thereafter progress through the cell cycle.…”

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

“…Scale bars: 50 μm Prolonged upregulation of cyclin D1, a rate-limiting cell cycle protein, after PH is required for adequate LR. 19 Figure 1), but did increase in a delayed fashion (7 d) in HET mice that survived PH. Altogether these data indicate that hepatocyte proliferation post PH is aborted and/or delayed in A20 HET livers.…”

Impact of differential cyclin D1 expression and localisation in prostate cancer

“…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). These collective observations have culminated in a model whereby androgen-mediated induction of cyclin D1 serves to activate CDK4 and promote cell cycle progression, but that accumulated cyclin D1 engages in a negative feedback loop to limit or modulate the response to androgen stimulation.…”