Nuclear cyclin D1: An oncogenic driver in human cancer

Abstract

Perturbations in the regulation of the core cell cycle machinery are frequently observed in human cancers. Cyclin D1 which functions as a mitogenic sensor and allosteric activator of CDK4/6, is one of the more frequently altered cell cycle regulators in cancers. Cyclin D1 is frequently overexpressed in cancers and its overexpression can be attributed to many factors including increased transcription, translation, and protein stability. Although cyclin D1 overexpression is clearly implicated in the affected cancers, overexpression of cyclin D1 is not sufficient to drive oncogenic transformation. Rather, emerging evidence suggests that nuclear retention of cyclin D1 resulting from altered nuclear trafficking and proteolysis is critical for the manifestation of its oncogenicity. This review provides a brief overview of current data documenting various mechanisms underlying aberrant cyclin D1 regulation in human cancers and their impact on neoplastic transformation.Work during the past two decades has provided a detailed molecular understanding of processes that drive cell cycle division. Early work resulted in the identification of the individual cyclin-dependent kinases that are activated during distinct cell cycle phases and contributed to our understanding of how phosphorylation of downstream targets in turn contributes to regulated cell cycle transitions. The recent generation of mice wherein individual cyclins or their cognate CDKs have been eliminated from the mouse germline has revealed the potential for significant redundancy with regard to CDK function and substrate regulation.While our fundamental understanding of the normal physiological functions of the cyclindependent kinase has increased dramatically, the potential pathological functions/activities remain to be established. This is particularly evident when one considers the potential contribution of G1 cyclins and CDKs to neoplastic transformation and growth. Regulation of G1 to S-phase progression is disrupted in nearly all cancers, due to its intimate function in the integration of growth factor signals with the cell cycle network. Of the G1 regulatory molecules, the cyclin D1/CDK4 complex is deregulated at a high frequency and is thought to contribute directly to neoplastic transformation and growth. Recent efforts have provided insights into the precise mechanisms whereby the cyclin D1-dependent kinase promotes tumorigenic growth and are discussed below.

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.…”

Effect of cigarette smoke exposure and mutant Kras overexpression on pancreatic cell proliferation

“…p53 is a tumor suppressor gene that promotes apoptosis but also inhibits cell proliferation (11). Cyclin D 1 regulates cyclin-dependent kinases (CDKs), which increase cell proliferation (12). Neither cigarette smoke exposure nor Kras overexpression, however, significantly affected the protein levels of TNFα, p53, or cyclin D 1 in the pancreas (Fig.…”

PP2ACdc55regulates G1cyclin stability

“…dephosphorylates the G 1 cyclin, Cln2, thus maintaining its stability, while SCF Grr1 is responsible for initiating phosphorylationdependent ubiquitylation and degradation, both of which are necessary for the inactivation of G 1 cyclin-cdk activity and subsequent activation of a cyclin-cdk activity required for G 2 -M. 9 As mammalian cyclin D1 is overexpressed in human cancers, 5,48,49 and its stability is associated with defects in SCF activity, 50 targeting PP2A through inhibiting its activity may represent a plausible therapeutic for cancer treatment.…”