Cell Cycle and Cancer
Authors: B. E. Clurman, J. M. Roberts
Journal: JNCI Journal of the National Cancer Institute (1995)

Is cancer a disease of the cell cycle? Recently, many laboratories have surveyed tumors and tumor cell lines for the presence of mutations in genes encoding cell cycle-related proteins (7). The combined results of these studies show that, as a group, mutations in cell cycle genes constitute the most common genetic change in tumor cells. In fact, it might turn out that almost 100% of tumors have mutations in one or another of the genes involved in controlling progression throughout the G! phase of the cell cycle. A defining characteristic of cancer cells is their ability to divide under conditions where their normal counterparts do not. This loss of growth control is manifest in many ways. Malignant cells may acquire independence from mitogenic signals that are normally required for cell cycle progression. They may no longer require substratum adherence or cell type-specific cytokines to enter the cell cycle, or they may cycle faster than normal cells. This unconstrained proliferation can be largely explained by the gain or loss of function of proteins that constitute the cell cycle machinery itself. At the core of the cell cycle engine is a group of protein kinases, the cyclin-dependent kinases (Cdks), that drive cell proliferation forward by phosphorylating specific substrates in a cell cycle-dependent fashion. Active Cdks are heterodimeric molecules that consist of a Cdk subunit and a cyclin subunit. To become active kinases, the Cdks must associate with cyclins as well as undergo an activating phosphorylation. Unique combinations of cyclins and Cdks assemble during each phase of the cell cycle, and the specific activities of these protein complexes are essential for progression through various cell cycle transitions. The D-type cyclins (Dl, D2, and D3) and cyclin E are the primary G) phase cyclins in mammalian cells (2). The D family of cyclins assemble into holoenzymes with the kinase catalytic subunits Cdk4 and Cdk6, while the principal partner of cyclin E is Cdk2. G] phase progression is also subject to negative regulation by a recently discovered group of molecules, the cyclin-dependent kinase inhibitors (CKIs) (i). In general, the relative abundance of CKJs present at any point in the cell cycle sets thresholds for cyclin-Cdk activation that must be overcome for the cell cycle to proceed. The CKJs fall into two classes. The first is the Kip/Cip family, which comprises three structurally related proteins (p21, p27, and p57) (4-17). The Kip/Cip proteins are all capable of binding to and inhibiting most cyclin-Cdk complexes (including the cyclin Dand cyclin E-Cdk complexes). Although the activities of these inhibitors are similar in many in vitro assays, their expression in vivo is under the control of different mitogenic and antimitogenic signals. For example, p21 is transcriptionally induced by the p53 protein, and it is an important mediator of cell cycle arrest imposed by p53 in response to DNA damage. p27, however, is not a p53 response gene but participates in the cell cycle arrest resulting from other physiologic signals, such as serum deprivation, contact inhibition, and transforming growth factor (TGF)-beta. Accordingly, much of the specificity of these molecules seems to reside in the upstream events that induce their expression in response to different signals.