Location, location, location: the role of cyclin D1 nuclear localization in cancer.

The control of cell proliferation is crucial in maintaining cellular homeostasis and loss of this mechanism is a principle hallmark of cancer cells. A primary target of growth factor signaling is the cyclin D1-dependent kinase (D1-CDK4/6) whose activity promotes G1 phase progression by phosphorylating the retinoblastoma protein (Rb) along with related pocket proteins 107 and p130, relieving inhibition of E2F family transcription factors. Cyclin D1 accumulation is regulated at multiple levels including transcription, post-translational activation and cellular localization throughout the cell cycle. While overexpression of cyclin D1 has been observed in a number of human cancers, mouse cancer models overexpressing D1 have fallen short of establishing a role for cyclin D1 in the initiation of malignant phenotypes suggesting an additional regulatory mechanism exists that prevents cyclin D1-driven cancer. This article will present an overview of current data investigating the regulation of cyclin D1 nuclear localization and the prevalence of these aberrations in cancer. Finally, future avenues of research involving cyclin D1 cellular localization and its regulation in cancer will be addressed. 2005 Wiley-Liss, Inc.