p21 in cancer: intricate networks and multiple activities

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Abstract
P21 came into the spotlight as a mediator of p53 tumour suppressor activity and as an inhibitor of cell cycle progression owing to its ability to inhibit the activity of cyclin-dependent kinase (CDK)–cyclin complexes and proliferating cell nuclear antigen (PCNA). The tumour suppressor activity of p21 stems from its role in inducing growth arrest, differentiation or senescence. Recently, it has become apparent that p21 is stimulated by many pathways that are independent of p53. p21 directly regulates gene expression and other cellular events through protein–protein interactions that are independent of CDKs and PCNA. Multiple transcription factors, ubiquitin ligases, and protein kinases regulate the transcription, stability and cellular localization of p21 thereby regulating its activity. Recent data suggest a tumorigenic role of p21 in certain contexts that relies on its ability to suppress apoptosis and promote the assembly of type-D cyclins with CDK4 and CDK6. Given that p21 is a tumour suppressor, but that it behaves as an oncogene in certain cellular contexts, targeting p21 or factors regulating its activity for therapeutic intervention is a promising but challenging task.