Dear Colleagues,

Deletion or mutations of TP53 gene is one of the most common genetic abnormalities in cancer. Since its discovery in 1979, the molecular and biological functions of p53 in cancer have been studied intensively. P53 senses stress signals such as DNA damage, activated oncogenes, nutrient deprivation, hypoxia, telomere attrition, oxidative stress and ribosome dysfunction. In response to potent stress signals, p53 triggers cell-cycle arrest, apoptosis and senescence to limit expansion of irreparable damaged or malignant cells. Under low-stress condition, p53 elicits responses such as DNA repair and antioxidation to promote survival and maintain genomic stability. Moreover, p53 also regulates angiogenesis, migration, metabolism and autophagy to restrict development of tumor. All these tumor suppressive activities mainly rely on transcription activation by p53, although p53 has other biochemical functions such as transcriptional repression and promotion of apoptosis by direct interaction with apoptotic regulators in the cytosol. The N-terminus of p53 contains two transcriptional activation domains (TADs), TAD1 (residues 1-40) and TAD2 (residues 40-60) which recruits both basal transcriptional machinery and co-activator complexes. The central core domain of p53 (residues 100-300) lies the DNA binding domain that direct the protein to p53-response elements (p53 RE). Most of the cancer associated p53 mutations are missense mutations in the DNA binding domain. The six most common p53 amino acid mutations in cancer (also known as “hotspots”) are R175, G245, R248, R249, R273 and R282. Other than inability to bind to DNA, these p53 mutants can confer gain of function which is linked to invasion and metastasis of cancer. Biological setting such as cell type and the nature of the stress determines the cell fate and transcriptional programs that are triggered by p53. In response to overt stress, apoptotic genes such as BAX, FAS, NOXA and PUMA or senescence genes such as CIP1, PAI1 and PML are activated to eradicate potentially oncogenic cells. Under lower stress conditions, DNA repair genes such as RRM2B, or antioxidatant genes such as SESN1, SESN2 and GPX1 are up-regulated to protect genome integrity. In addition, p53 inhibits glycolysis through TIGAR, promotes oxidative phosphorylation via SCO2 and blocks angiogenesis by activation of TSP-1. More than 125 direct p53-target genes have been identified and chromotin immunoprecipitation (ChIP) assays identified thousands of p53-binding sites on the genome. However, none of the p53-target gene knockout mouse model to date recapitulates the high tumor-penetrance and short tumor-latency in TP53 knockout mice suggesting that multiple p53-target genes controls tumor suppressive function by p53 in concert. In general, tumor cells containing functional p53 are more sensitive to radiation therapy or chemotherapy. However, recent evidence suggested that wild type p53 can engage into a pro-survival pathway to counteract apoptosis in some cases. Nevertheless, reactivation or restoration of functional p53 has been an attractive approach of chemotherapy and under development in the recent years. The strategies includes stabilization of wild type p53 such as inhibiting the activity of MDM2, an E3 ubiquitin ligase of p53 and interference of MDM2-p53 interaction; enhancement of DNA binding activity of wild type p53 by inactivating SIRT1 deacetylase as well as targeting mutant p53 to restore native conformation and transcription activation. Several small molecules have been discovered based on these approaches and are under investigation to test their efficacy as anti-cancer agents. Further studies on p53 mechanism of action and functional role in cancer will continue. These advances of knowledge will be helpful to gain insights on rational design of p53-based therapy in the future.

Prof. Dr. Yun Yen
Guest Editor

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