CDK-independent activities of D type cyclins

Abstract

D type cyclins are major downstream targets of extracellular signaling pathways which act to transduce mitogenic signals to the cell cycle machinery. Transcriptional induction of D type cyclins occurs in response to a wide variety of mitogenic stimuli, including the Ras signaling cascade [1,2] and the APC-L-catenin-Tcf/Lef pathway [3]. In addition, cyclin D1 protein turnover and subcellular localization are highly regulated during the cell cycle [4]. Because of their critical role in linking cytoplasmic signals to nuclear responses it is perhaps not surprising that D type cyclins are frequent targets of mutagenesis in various types of cancer [5]. Biochemically, D-type cyclins act, in part, as regulatory subunits of cyclin-dependent kinases (CDKs) 4 and 6. Cyclin D/CDK4/6 complexes, together with cyclin E/CDK2, cause phosphorylation of the retinoblastoma family of tumor suppressor proteins (pRb, p107 and p130) in the G1 phase of the cell cycle, resulting in abrogation of their growth-inhibitory activity (see [6] for a review). The ability of D type cyclins to interact with and activate their CDK partners is antagonized by the p16INK4 family of CDK inhibitors. Mutations in p16INK4A are found in a variety of spontaneous tumors and heterozygosity for p16INK4A in the germ line predisposes to melanoma [7]. It is generally believed that this p16INK4A-cyclin D1-pRb pathway is deregulated in virtually all human cancers and this notion underscores the critical role of D type cyclins as CDK regulators in growth control. However, in the past 2 years it has become apparent that D type cyclins also have activities that are unrelated to their function as CDK regulatory subunits. These novel CDK-independent activities of D type