Introduction

The cell division cycle is a carefully choreographed series of events that culminates in cell division. The fundamental task of the cell cycle is to faithfully replicate DNA and to equally distribute identical chromosome copies to two daughter cells. Genetic defects affecting the cell cycle machinery contribute to uncontrolled cell division, the hallmark of cancer. Cancer cells accumulate cell cycle alterations, abandon cell cycle control and tend to remain in cycle. An appreciation of the molecules that regulate the cell cycle is central to our understanding of the fundamental cell division process and also pinpoints the mechanisms that lead to cancer.

Cell Cycle Phases

The fundamental cell cycle events of DNA replication and cell division occur during interphase and mitosis, respectively. Interphase is the longer phase and includes the sub-phases G1, S and G2.

Cell Cycle

G1 PHASE

During the G1 phase, cells respond to extracellular signals by advancing towards another division or withdrawing from the cycle into a resting state (G0). The decision to divide occurs as cells pass a restriction point late in G1, after which they become refractory to extracellular growth regulatory signals and commit to division. 

Passage through the restriction point is controlled by cyclin dependent kinases (CDKs) that are sequentially regulated by cyclins D, E and A. As cells enter the cycle, D-type cyclins are induced in response to growth factor stimulation, and assemble with their catalytic partners, CDK4 and CDK6. Cyclin D-dependent kinases phosphorylate the retinoblastoma tumour suppressor protein, and this modification is required for G1 exit. While hypophosphorylated, pRb and its homologues (p107, p130) bind a family of transcriptional regulators, collectively termed the E2Fs, converting them into repressors that limit the expression of E2F target genes. Phosphorylation of pRb, initially by the cyclin D-dependent kinases and then followed by the cyclin E-CDK2 complex, releases these E2Fs, enabling them to transactivate the same genes. These E2F-regulated gene products are important for S phase entry. Specific inhibitors of CDK4 and CDK6, the INK4 proteins, can directly block cyclin D-dependent kinase activity and cause cell cycle arrest in the G1 phase. The INK4 proteins (p15^INK4b, p16^INK4a, p18^INK4c and p19^INK4d) bind and inhibit CDK4 and CDK6. Disruption of the retinoblastoma pathway, by p16^INK4a inactivation, loss of pRb or overexpression of cyclin D1, is common in cancer.

S PHASE

Once cells enter S phase, cyclin E and E2F activities are inactivated by ubiquitin-dependent proteolysis and cyclin A-CDK2 driven phosphorylation, respectively. Cyclin A-associated kinase activity is required for entry into S phase, completion of S phase and entry into mitosis. Cyclin A colocalises with sites of DNA replication, suggesting a role in DNA synthesis. Cyclin D-, E-, and A-dependent kinases are negatively regulated by a distinct family of CDK inhibitors that include at least three proteins, p21^Waf1, p27^Kip1 and p57^Kip2. The remarkable feature in relation to cancer is the inducibility of p21^Waf1 by the tumour suppressor, p53.

Similar to G1, G2 is an intermediate gap phase. It contains a checkpoint that responds to DNA damage and causes a delay to allow DNA repair before entry into mitosis. Mitosis is regulated by CDK1 in association with cyclins A, B1 and B2. These cyclin-CDK1 complexes phosphorlate cytoskeletal proteins such as lamins, histone H1, and possibly components of the mitotic spindle. For cells to exit mitosis, cyclins A and B must be degraded.