Table 1.

Known functions of wild-type p53.

Function	Summary—Key Regulatory Functions	Reference
Homeostasis regulators	p53 is a key regulator of replication homeostasis within a DNA restart network and is essential for DNA methylation homeostasis in stem cells. It also plays a key role in the regulation of metabolic homeostasis. The function of p53 in cellular energy homeostasis and metabolism is emerging as a critical factor for tumor suppression.	[62,72,83,84,85]
Cell cycle arrest	One of the best-understood function of p53 is to promote cell cycle arrest. Cell cycle arrest by p53 is mainly mediated by the transcriptional activation of p21/WAF1 and is reversible after downregulation of p53.	[72,83,86,87,88,89,90]
Apoptosis	It has been confirmed in many studies that induction of apoptotic death in nascent neoplastic cells is the principal mechanism by which p53 suppresses tumor development. p53 induces apoptosis in nontransformed cells mostly by direct transcriptional activation of the pro-apoptotic BH3-only proteins PUMA and (to a lesser extent) NOXA.	[86,87,91,92,93]
Cellular senescence	Chronic p53 activation can result in senescence of tumor cells. Senescent cells have unique features, such as large cell size, active autophagy, high lysosomal SA-b-gal activity, and secretion of proinflammatory cytokines. Senescence is a unique state of cell cycle arrest that is highly stable but is not completely irreversible. Through the induction of senescence, p53 promotes and achieves permanent inhibition of cell proliferation.	[86,87,93,94,95,96,97,98,99]
Cellular quiescence	p53 is activated during both quiescence and senescence. Evidence suggests that p53 activation contributes to the quiescent growth arrest and is a reversible process.	[100,101,102].
Proliferation/survival	There is a strong direct correlation between accumulation of p53 protein and tumor proliferation rate. Expression of mutant p53 protein was associated with high tumor proliferation rate, early recurrence, and death in breast cancer. Recently, it was noted that p53 can also contribute to cell survival.	[86,90,91,99,103,104]
Autophagy	In most cases, p53 positively regulates autophagy in tumor cells by inhibiting mTOR pathways via the activation of AMPK. p53 also promotes autophagy by inducing various autophagy-related genes. Autophagy is considered a tumor suppressive mechanism that removes unfolded proteins, damaged cellular components, and damaged organelles to maintain cellular homeostasis.	[96,105,106,107,108,109,110,111]
Metabolism	p53 promotes oxidative phosphorylation and dampens glycolysis in cells; disruption of this balance is associated with mutations in p53 and oncogenic transformation. P53 plays a role in alterations seen in glycolysis, gluconeogenesis, and aerobic respiration. Altered metabolism can contribute to malignant transformation, and cancer cells become dependent on these changes. p53 regulates various metabolic pathways, helping to balance glycolysis and oxidative phosphorylation, limiting the production of reactive oxygen species, and contributing to the ability of cells to adapt to and survive mild metabolic stresses.	[72,77,84,87,88,99,112,113]
DNA repair	p53 plays a prominent role as a facilitator of DNA repair by halting the cell cycle to allow time for the repair machinery to restore genomic stability; for example, p53 coordinates DNA base excision repair in the cells, and this mechanism is impaired in p53-inactivated cells. Within a DNA restart network, p53 functions as a keystone regulator in DNA replication homeostasis.	[85,114]
Oncogenic functions	p53wt is a tumor suppressor gene; mutations in this gene promote oncogenic capacity. Thus, mutant p53 is an actionable target of clinical antitumor therapies. p53 loss of heterozygosity (LOH ) is a critical prerequisite for missense mutant p53 stabilization and gain of function in vivo.	[92,115,116,117]
Epigenomic regulator	p53 is not only a pivotal guardian of genomic stability, but also an epigenetic regulator. Epigenomic regulation is a new function of p53, contributing to its tumor suppressor activity. It is thought that the ability of p53 to maintain DNA methylation balance is an important contributor to its tumor suppressor capacity and that loss of p53 may result in cancer initiation by increasing cellular heterogeneity and epigenetic promiscuity.	[62,93,104,118,119]
Regulating multiple tumor suppressor genes	Under normal low-stress conditions, p53wt is capable of maintaining the expression of a group of important tumor suppressor genes at baseline, which could contribute to p53-mediated tumor suppression. p53 mutations, with inactivation of multiple tumor suppressor genes in parallel, could lead to the high frequency of p53 mutations in cancer.	[120]
Mutant p53 functions	Unidentified mechanisms by which mutp53 confers oncogenic functions by promoting cancer cell adaptation to metabolic stresses.	[88,92,121]
Non-canonical cell death	Transcriptional regulation of downstream targets: caspase-independent apoptosis, autophagy, ferroptosis, mitotic catastrophe, paratosis, pyrotosis, efferocytosis (clearing dead cell debris).	[122]