p53

p53 is a tumor suppressor protein encoded by the TP53 gene in humans. It functions as a transcription factor activated by cellular stress such as DNA damage, oncogene signaling, and hypoxia. The human protein is about 393 amino acids long, with an N-terminal transactivation domain, a central DNA-binding domain, and a C-terminal regulatory region. p53 helps maintain genomic stability by preventing propagation of damaged cells.

Upon activation, p53 induces cell cycle arrest mainly through activation of CDKN1A (p21), leading to G1/S arrest and allowing DNA repair. It also promotes DNA repair by regulating genes such as GADD45, and can trigger apoptosis via pro-apoptotic BCL-2 family members (PUMA, NOXA, BAX) and the mitochondrial pathway. p53 also influences senescence and metabolic processes that limit tumor growth.

p53 activity is tightly regulated by MDM2, an E3 ubiquitin ligase that targets p53 for degradation. Stress signals promote p53 stabilization through post-translational modifications (phosphorylation, acetylation) that disrupt MDM2 binding. The ARF tumor suppressor can inhibit MDM2, enhancing p53 responses. Various cofactors and alternative isoforms further modulate p53 function.

Mutations in TP53 are among the most common in human cancers. Most are missense mutations in the DNA-binding domain that impair transcriptional activation. Some mutants exert dominant-negative effects or gain-of-function properties, contributing to oncogenesis through altered gene regulation and interaction networks.

In addition to the canonical isoform, several transcriptional and translational variants arise from alternative splicing and initiation, yielding p53 isoforms that can modulate the vigor and context of responses. p53 can also act at mitochondria to promote apoptosis independently of transcription.

Clinical relevance and therapy. p53 status informs prognosis and treatment decisions. Approaches to restore p53 activity include MDM2 inhibitors for tumors with wild-type TP53 and small molecules that reactivate mutant p53; gene therapy and combination strategies are under investigation.