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.The importance of cell cycle mediators to human carcinogenesis is now well established. In particular, critical genes that regulate cell cycle checkpoints have been demonstrated to be lost and/or have loss of function in many different human cancers. However, it has only recently been appreciated that dysfunction or loss of many of these same genes can also mediate resistance versus sensitivity to currently used cancer therapies. In this review, we focus on two important cell cycle regulators -the cyclin-dependent kinase (CDK) inhibitors p21 (CDKN1A) and p27 (CDKN1B) -by discussing their early discovery as mediators of cell cycle checkpoints and subsequent work showing how their loss or dysfunction leads to carcinogenesis and, more recently, resistance to therapeutic drugs. We also briefly discuss their paradoxical effects as cell cycle and tumour promoters.
Cell cycle, cyclins, CDKs and CDK inhibitorsThe cell cycle comprises a very carefully orchestrated set of events that can lead to cell proliferation, senescence or apoptosis. Cells progress through the various phases of the cell cycle via the interactions of different cyclins with their respective CDK subunits (Fig. 1). The name cyclin comes from the fact that these proteins were first identified as molecules that accumulated and were then degraded at distinct points during the cell cycle of embryonic sea urchin eggs (Ref. 1). There are now several recognised classes or types of cyclins, active in different stages of the cell cycle. The D-and E-type cyclins are associated with the G1-S phase transition of the cell cycle (Refs 2,3). Human cyclin D1 (CCND1; also called PRAD1 and BCL-1) and E were identified from mRNAs able to restore cyclin function in cyclin-deficient yeast (Refs 4,5). Cyclin D1 quickly generated interest when it was mapped to chromosomal locus 11q13 close to a region known to be a breakpoint for certain chromosomal inversions