P21 and p27: roles in carcinogenesis and drug resistance

Abstract

Human cancers arise from an imbalance of cell growth and cell death. Key proteins that govern this balance are those that mediate the cell cycle. Several different molecular effectors have been identified that tightly regulate specific phases of the cell cycle, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors. Notably, loss of expression or function of two G1-checkpoint CDK inhibitors - p21 (CDKN1A) and p27 (CDKN1B) - has been implicated in the genesis or progression of many human malignancies. Additionally, there is a growing body of evidence suggesting that functional loss of p21 or p27 can mediate a drug-resistance phenotype. However, reports in the literature have also suggested p21 and p27 can promote tumours, indicating a paradoxical effect. Here, we review historic and recent studies of these two CDK inhibitors, including their identification, function, importance to carcinogenesis and finally their roles in drug resistance.

Figure 1. Cell cycle progression is regulated by cyclin-CDK complexes

Following a mitogenic stimulus, the decision to enter the cell cycle is regulated by complexes of cyclin-B-CDK1 and cyclin-C-CDK3 complexes (not shown). Next, during G1, D- and E-type cyclins are upregulated and assemble with their respective CDK binding partners. The cyclin-D-CDK4/6 and cyclin-E-CDK2 complexes then phosphorylate the retinoblastoma protein (pRB), thus inactivating it and releasing the transcription factor E2F from its inhibition. E2F then activates a variety of growth-promoting genes, which sends the cell cycle into the synthesis (S) phase. The cyclin-B-CDK1 complex continues to inhibit pRB at the S-G2 and G2-mitosis (M) checkpoints via phosphorylation to ensure completion of the cell cycle. Finally, following dephosphorylation of pRB, cells exit the M phase and pRB once again inhibits E2F. The CDK inhibitors p21 and p27 regulate the cell cycle by inhibiting the functions of the various CDK proteins as indicated. Abbreviations: CDK, cyclin-dependent kinase; P, phosphorylation.

Figure 2. CDK inhibitors are regulated by phosphorylation within the nucleus

p21 or p27 protein is able to interact with cyclin-CDK complexes within the nucleus and hence regulate the cell cycle. p21 and p27 are themselves regulated either by sequestration via cyclin-CDK complexes, or by phosphorylation on serine/threonine (S/T) residues by enzymes such as AKT. In the case of p27, the tyrosine kinase SRC can also phosphorylate this protein. Following phosphorylation, p21 or p27 exit the nucleus and enter the cytoplasm, where they are not able to bind nuclear cyclin-CDK complexes and can then be degraded. Abbreviations: P, phosphorylation; S/T, serine/threonine; Y, tyrosine.