The Dual Role Played by p21 May Influence the Apoptotic or Anti-Apoptotic Fate in Cancer

Abstract

p21 is a cyclin-dependent kinase inhibitor that is activated in response to different stress stimuli and could act as cell cycle suppressor. p21 can bind and inhibit cyclin-dependent kinase/cyclin complexes to mediate growth arrest in G1 and G2 phases. This condition enables DNA repair and suggests that p21 could have a role of tumour suppressor. p21 is one of the transcriptional targets of p53, a protein up-regulated after cellular stress stimuli. Besides the classical p53-dependent activation, p21 transcription can be achieved by other regulators as Sp1, STAT and AP2 in a p53-independent manner. Depending on cell type and cellular conditions p21 can have anti-apoptotic or pro-apoptotic functions being involved either in tumourigenesis or in tumour suppression. The function exerted is based on subcellular localization. In the nucleus p21 inhibits proliferation by blocking the cyclin dependent kinases while in the cytoplasm it acts inhibiting pro-apoptotic protein determining cell death inhibition. The different subcellular localization is related to different prognostic role of p21 in cancer and the cellular context in which it is expressed determines if it can be considered as a specific therapeutic target or as a marker of poor prognosis. This review focuses on the recent understanding of the functions of p21 with particular attention to the dual role detected in cancer where p21 can act as tumour suppressor promoting apoptosis or as oncogene preventing it.