The Cell Cycle and Cancer

A unique feature of cancer cells is high, indefinite cellular proliferation that continues without regard for the surrounding environment and the regulatory mechanisms that exist in normal cells. In normal tissues, cell division occurs in the context of a series of sequential biological events known as the cell cycle, which is composed of four different phases (Figure 1). DNA replication occurs in the so-called S (synthesis) phase, and cell division occurs in the M (mitosis) phase. These two main activities are preceded by two gap phases: G1 to prepare cells for DNA synthesis, and G2 to allow cells the opportunity to check the integrity of the newly synthesize DNA and to prepare cell division. Phase transitions are controlled by a series of serine/threonine kinases called cyclin-dependent kinases (CDKs) and their regulatory subunits named cyclins. Misregulation the cell cycle is a general event in diseases of uncontrolled cell growth and some of the most common alterations of this pathway are discussed in the following sections. The G1/S transition and the increase of activity of cyclin-dependent kinases

Cells entering the G1 phase will actively prepare to divide (newly synthesized proteins are produced, the cell size increases), until a certain point called the G1 checkpoint. This crucial checkpoint is controlled by the retinoblastoma tumor suppressor gene product (Rb), which is a transcriptional regulator. This protein imposes a block on G1 progression that is released by its phosphorylation by Cdk4/cyclin D1, Cdk6/cyclin D3, and Cdk2/cyclin E. Hyperphosphorylated Rb (pRb) dissociates from the transcription factors of the E2F-DP family (principally E2F1, 2, and 3) making these proteins available to direct the expression of proteins essential for DNA synthesis such as cyclin A, dihydrofolate reductase, thymidine kinase, thymidylate synthase, or DNA polymerase-a. The activity of the CDKs is tightly regulated by endogenous inhibitors of Cdk/cyclin complexes. Thus, the p21cip1, p27kip1, and p57kip2 gene products can bind and inhibit all Cdk/cyclin D, E, and A complexes, and the products of the INK4 gene (p16Ink4a, p15Ink4b, p18Ink4c, and p16Ink4d) have the ability to interact specifically with CDK4 and 6.

The G1 checkpoint is often deficient in human tumors, often due to deregulation or absence of the Rb protein. Although germline mutations in the RB gene cause the highly penetrant hereditary retinoblastoma,84 the frequency of RB mutation is low among the sporadic cancers; however, it has been reported in osteosarcomas, small cell lung carcinomas, and breast carcinomas. Rb protein inactivation, found in a wide variety of human cancers,85 may be the result of three possible causes. First, the Rb protein can be sequestered from its physiological partners, when bound to viral oncoproteins, such as the SV40 T antigen, the adenovirus E1A protein, or the papilloma E7 protein.86 These events are frequently observed in human cervical tumors. The second cause, and probably the most common one, is the o

Extracellular signaling Growth regulating factors

Early G1

Late G1

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