Tumor protein p53 (p53) (p53)

Tumor protein p53 (TP53) is a pivotal tumor suppressor protein that acts as a transcription factor, regulating the expression of genes involved in cell cycle arrest, DNA repair, senescence, and apoptosis (UniProt: P04637). Known as the "guardian of the genome," p53 is activated in response to various cellular stresses, such as DNA damage, hypoxia, and oncogene activation, to maintain genomic integrity (StatPearls: NBK562268). In approximately half of all human cancers, p53 function is lost through direct mutation of the TP53 gene, while in others, it is suppressed by the overexpression of negative regulators like MDM2 and MDMX (PubMed: 31064754). Therapeutic strategies targeting the p53 pathway focus on restoring its tumor-suppressive activity, either by inhibiting the MDM2-p53 interaction in wild-type tumors or by refolding mutant p53 proteins into their active conformation (PubMed: 33073387). MDM2 inhibitors, such as idasanutlin and navtemadlin, have shown clinical activity but are often limited by dose-dependent hematological toxicities like thrombocytopenia (PubMed: 32884383). Additionally, mutant p53 reactivators like eprenetapopt are being investigated in hematologic malignancies to overcome the loss of function caused by TP53 mutations (PubMed: 33073387). The pathway's complexity and the potential for selecting resistant clones remain significant hurdles in the development of effective p53-targeted therapies.

Other names

TP53Cellular tumor antigen p53Antigen NY-CO-13Phosphoprotein p53Tumor suppressor p53p53 tumor suppressor pathway

The primary mechanisms of action include the inhibition of the MDM2-p53 protein-protein interaction to prevent p53 degradation in wild-type tumors, and the use of small molecules to restore the functional DNA-binding conformation of mutant p53 proteins (PubMed: 31064754, PubMed: 33073387).