The p53 protein is a tumor suppressor that induces apoptosis in response to oncogenic stress. Loss of p53 function is a key factor in malignant progression, occurring through mutations in the TP53 gene or defects in signaling pathways upstream or downstream of p53. Mutations in TP53 are found in about half of all cancers, often resulting in mutant p53 proteins with transforming activity. p53-induced apoptosis depends on its ability to activate gene expression, although transcriptionally independent activities can also contribute. The apoptotic and cell-cycle arrest activities of p53 can be separated, and specific apoptotic cofactors are being identified. Regulation of p53's apoptotic function involves selective activation of apoptotic target genes, with cofactors like JMY, ASPP, and p63/p73 playing key roles. Phosphorylation and acetylation of p53 regulate its ability to activate apoptotic target genes. In tumors with wild-type p53, defects in apoptotic cofactors can hinder the apoptotic response, making them potential therapeutic targets. p53 is activated by stress signals, leading to cell-cycle arrest, senescence, differentiation, or apoptosis. p53 can also repair genotoxic damage, but in most cases, it leads to irreversible cell growth inhibition through apoptosis. p53 is regulated by proteins like MDM2, which inhibits its activity. Mutations in p53 can lead to dominant-negative inhibition of wild-type p53 or gain of function, contributing to tumorigenesis. p53's apoptotic activity is regulated by various cofactors and post-translational modifications. The choice of response to p53 activation depends on factors such as cell type, environment, and oncogenic alterations. p53 can induce apoptosis through mitochondrial and death-receptor pathways, and its activity is regulated by survival signals and other factors. Reactivation of p53 function in cancer cells is a promising therapeutic strategy, as it can selectively induce apoptosis in tumor cells while sparing normal cells. Small molecules and peptides that restore mutant p53 function are being explored for cancer therapy. Understanding the mechanisms of p53 regulation and its interactions with cofactors is crucial for developing effective therapies. The identification of p53 cofactors and their roles in apoptosis provides new targets for therapeutic intervention. The interplay between p53 and other signaling pathways, such as E2F and NF-κB, highlights the complexity of p53's functions in cancer. Overall, p53's role in cancer is multifaceted, and its regulation is essential for developing targeted therapies.The p53 protein is a tumor suppressor that induces apoptosis in response to oncogenic stress. Loss of p53 function is a key factor in malignant progression, occurring through mutations in the TP53 gene or defects in signaling pathways upstream or downstream of p53. Mutations in TP53 are found in about half of all cancers, often resulting in mutant p53 proteins with transforming activity. p53-induced apoptosis depends on its ability to activate gene expression, although transcriptionally independent activities can also contribute. The apoptotic and cell-cycle arrest activities of p53 can be separated, and specific apoptotic cofactors are being identified. Regulation of p53's apoptotic function involves selective activation of apoptotic target genes, with cofactors like JMY, ASPP, and p63/p73 playing key roles. Phosphorylation and acetylation of p53 regulate its ability to activate apoptotic target genes. In tumors with wild-type p53, defects in apoptotic cofactors can hinder the apoptotic response, making them potential therapeutic targets. p53 is activated by stress signals, leading to cell-cycle arrest, senescence, differentiation, or apoptosis. p53 can also repair genotoxic damage, but in most cases, it leads to irreversible cell growth inhibition through apoptosis. p53 is regulated by proteins like MDM2, which inhibits its activity. Mutations in p53 can lead to dominant-negative inhibition of wild-type p53 or gain of function, contributing to tumorigenesis. p53's apoptotic activity is regulated by various cofactors and post-translational modifications. The choice of response to p53 activation depends on factors such as cell type, environment, and oncogenic alterations. p53 can induce apoptosis through mitochondrial and death-receptor pathways, and its activity is regulated by survival signals and other factors. Reactivation of p53 function in cancer cells is a promising therapeutic strategy, as it can selectively induce apoptosis in tumor cells while sparing normal cells. Small molecules and peptides that restore mutant p53 function are being explored for cancer therapy. Understanding the mechanisms of p53 regulation and its interactions with cofactors is crucial for developing effective therapies. The identification of p53 cofactors and their roles in apoptosis provides new targets for therapeutic intervention. The interplay between p53 and other signaling pathways, such as E2F and NF-κB, highlights the complexity of p53's functions in cancer. Overall, p53's role in cancer is multifaceted, and its regulation is essential for developing targeted therapies.