p21

p21, also known as p21^WAF1/CIP1 or CDKN1A, is a cyclin-dependent kinase inhibitor in humans encoded by the CDKN1A gene. It is a key regulator of cell cycle progression, acting to restrain cells from advancing from G1 to S phase and, in some contexts, to S phase. The protein can interact with multiple cyclin-CDK complexes, including CDK2, CDK4, and CDK6, thereby inhibiting their kinase activity. Through binding to proliferating cell nuclear antigen (PCNA), p21 also influences DNA replication and repair, contributing to genomic stability.

Expression of p21 is primarily induced by the tumor suppressor p53 in response to DNA damage, providing a mechanism for cell cycle arrest to allow repair. However, p21 can also be regulated independently of p53 by various signaling pathways, including TGF-β/Smad and other transcriptional networks. The activity and stability of p21 are modulated by post-translational modifications such as phosphorylation, acetylation, and ubiquitination; degradation is mediated in part by the SCFSkp2 ubiquitin ligase complex.

p21 is found mainly in the nucleus, where it blocks CDK activity, but it can also localize to the cytoplasm under certain conditions. Cytoplasmic p21 has been linked to anti-apoptotic and other non-canonical functions, reflecting context-dependent roles in cells.

In cancer biology, p21 contributes to tumor suppression by enforcing cell cycle arrest, yet its role is complex: loss of p21 can lead to genomic instability, while sustained p21 expression can promote cell survival and therapy resistance in some contexts. Beyond cancer, p21 participates in cellular senescence, differentiation, and DNA repair processes.