An integrated view of cyclin E function and regulation

Abstract

Cancers of diverse cell lineages express high levels of cyclin E, and in various studies, cyclin E overexpression correlates with increased tumor aggression. One way that normal control of cyclin E expression is disabled in cancer cells is via loss-of-function mutations sustained by FBXW7. This gene encodes the Fbw7 tumor suppressor protein that provides substrate specificity for a ubiquitin ligase complex that targets multiple oncoproteins for degradation. Numerous other mechanisms besides Fbw7 mutations can deregulate cyclin E expression and activity in cancer cells. Recent reports demonstrate that inappropriate cyclin E expression may have far-reaching biological consequences for cell physiology, including altering gene expression programs governing proliferation, differentiation, survival and senescence. In this review, we discuss the function of mammalian cyclin E in the context of these new data as well as the complex network that connects cyclin E functions to the cellular controls regulating its expression and activity.

Figure 1

Overview of cyclin E function, regulation and their interrelatedness. Cyclin E-Cdk2 regulates multiple cellular processes. The activity and expression of cyclin E is subject to a regulatory network comprised of Cdk inhibitors, the p53 and Fbw7 tumor suppressor pathways, signal transduction pathways and microRNAs. The kinase activity of cyclin E-Cdk2 is depicted by dark arrows directed at substrates. A dashed arrow denotes the proposed kinase-independent function of cyclin E. Within the SCF^Fbw7 pathways, “p” signifies CPD phosphorylation by the indicated kinase.