Cellular tumor antigen p53 (p53) and Cyclin-dependent kinase inhibitor 1 (p21) (p53-p21)

The p53-p21 axis is a fundamental signaling pathway responsible for maintaining genomic integrity and regulating the cell cycle. Cellular tumor antigen p53 (TP53) acts as the 'guardian of the genome' by sensing DNA damage and stress, subsequently functioning as a transcription factor to induce the expression of Cyclin-dependent kinase inhibitor 1 (p21/CDKN1A) [4, 8]. p21 then binds to and inhibits cyclin-dependent kinases (CDKs), leading to cell cycle arrest in the G1 and G2 phases, which allows for DNA repair or triggers senescence and apoptosis if the damage is irreparable [8, 12]. Dysregulation of this axis, often through TP53 mutations or MDM2 overexpression, is a hallmark of many cancers, leading to uncontrolled proliferation and resistance to cell death [1, 13]. Therapeutic strategies focus on restoring p53 function using MDM2 inhibitors (e.g., idasanutlin) to prevent p53 degradation or small molecules (e.g., eprenetapopt) that refold mutant p53 proteins [13, 15]. While promising, targeting this axis faces significant challenges, including hematological toxicities like thrombocytopenia and the potential for selecting resistant p53-mutant clones in heterogeneous tumors [13, 14].

Other names

TP53CDKN1AWAF1CIP1p53-p21 axisp53-p21 signaling pathwayp53-p21-RB pathway

Inhibition of MDM2-p53 interaction, stabilization of wild-type p53, pharmacological reactivation of mutant p53, induction of p21 expression, and inhibition of cyclin-dependent kinases.