The p53-dependent G1 checkpoint

Checkpoint controls exist throughout the cell cycle to ensure that the phases are completed in an orderly and timely manner. These surveillance programs are not essential to the working of the cell cycle, but are crucial in maintaining genomic stability and act as brakes in response to stress or damage.

The p53 gene is a key checkpoint regulator and is the most frequently mutated gene in human cancer. Although p53 is ordinarily a short-lived protein, it is stabilised and accumulates in cells exposed to a variety of cellular stresses, including DNA damage, transcription inhibition, oncogene expression, viral infection and heat shock. It has been suggested that these diverse signals activate p53 by disrupting the nucleolus. Alterations affecting the nucleolus may prevent p53 nuclear export via the nucleolus or induce the release of nucleolar proteins, such as p14ARF and L11 that directly stabilise p53. The p53 protein is transcription factor and transactivates hdm2, an amplifiable proto-oncogene product that promotes the ubiquitination, nuclear export and degradation of p53. In some cell types, p53 induces apoptosis by directly activating death genes, such as Bax or downregulating survival genes, such as Bcl-2. p53 also transactivates the CDK inhibitor p21Waf1, which is at least partially responsible for p53-mediated G1 arrest. Consistent with the idea that p53-induced p21Waf1 can limit the hyperphosphorylation of pRb, loss of pRb can bypass p53-mediated G1 arrest. Thus, co-operation between the pRb and p53 pathways induces G1 arrest and apoptosis in response to DNA damage. 

References:

Johnson DG and Walker CL. Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol 1999; 39:295-312

Rubbi CP and Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J 2003; 22:6068-6077.

Sherr CJ and McCormick F. The RB and p53 pathways in cancer. Cancer Cell 2002; 2:103-112