p53p21

p53p21 refers to the functional connection between the tumor suppressor p53 and the cyclin-dependent kinase inhibitor p21. In response to cellular stress such as DNA damage or oncogene activation, p53 is stabilized and acts as a transcription factor to induce p21 expression. The p53-p21 axis is a major mechanism by which cells enforce cell cycle arrest and maintain genomic integrity.

Mechanistically, p53 binds to response elements in the CDKN1A promoter, increasing p21 mRNA and protein levels. p21 inhibits several cyclin-dependent kinases, notably CDK2-cyclin E and CDK4/6-cyclin D complexes. This prevents phosphorylation of the retinoblastoma protein, blocking E2F target gene activation and arresting cells in G1. If DNA damage is repaired, p53 and p21 levels decline and the cell cycle resumes; if damage is irreparable, the pathway can contribute to senescence or apoptosis depending on context.

The p53-p21 axis is central to genome maintenance and tumor suppression, coordinating cell cycle control with DNA repair pathways. p21 also participates in broader p53-independent responses, and its activity can influence outcomes such as senescence and differentiation, with effects that vary by cell type and stress condition.

Regulation of the axis involves tight control of p53 stability by the MDM2–p53 feedback loop; p53 activation leads to p21 expression, which in turn helps restrain proliferation. p21 itself is subject to ubiquitin-mediated degradation and can be regulated by p53-independent signals and post-translational modifications, affecting its subcellular localization and function.

In cancer, disruptions of the p53-p21 axis—through TP53 or CDKN1A mutations or pathway dysregulation—contribute to unchecked growth. Therapeutic strategies include restoring p53 function, enhancing p21 activity, or using CDK inhibitors to emulate p21-mediated cell cycle arrest. See also p53, CDKN1A, cell cycle arrest, and DNA damage response.