p21Cip1

p21Cip1, also known as p21^Cip1/Waf1, is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors and is encoded by the CDKN1A gene. The protein is approximately 21 kDa in size and functions primarily as a regulator of cell cycle progression by binding to and inhibiting multiple cyclin-CDK complexes, especially cyclin D-CDK4/6 and cyclin E-CDK2. Through these interactions, p21 enforces a G1/S checkpoint in response to various cellular stresses, including DNA damage.

Expression and regulation of p21 are tightly controlled. p21 is transcriptionally induced by the tumor suppressor p53 in response to DNA damage, contributing to cell cycle arrest and DNA repair. It can also be upregulated via p53-independent pathways, such as signaling through transforming growth factor beta (TGF-β). Post-translationally, p21 levels are modulated by ubiquitin-proteasome–mediated degradation, with the SCF^Skp2 complex playing a key role in reducing p21 to permit cell cycle progression.

Beyond CDK inhibition, p21 binds to proliferating cell nuclear antigen (PCNA) and influences DNA replication and repair processes. It participates in cellular senescence and differentiation programs. Localization affects function: nuclear p21 promotes cell cycle arrest, whereas cytoplasmic p21 can modulate apoptosis and cell migration in certain contexts.

Clinical relevance of p21 includes its use as a biomarker in cancer, where its expression and regulation correlate variably with prognosis depending on tumor type and p53 status. Because p21 integrates cell cycle control with DNA damage responses, it remains a focus of research in oncology and aging-related studies.