Abstract
The tumor suppressor p53 and its homologues, p63 and p73, play a pivotal role in the regulation of the DNA damage response, cellular homeostasis, development, aging, and metabolism. A number of mouse studies have shown that a genetic defect in the p53 family could lead to spontaneous tumor development, embryonic lethality, or severe tissue abnormality, indicating that the activity of the p53 family must be tightly regulated to maintain normal cellular functions. While the p53 family members are regulated at the level of gene expression as well as post-translational modification, they are also controlled at the level of protein stability through the ubiquitin proteasomal pathway. Over the last 20 years, many ubiquitin E3 ligases have been discovered that directly promote protein degradation of p53, p63, and p73 in vitro and in vivo. Here, we provide an overview of such E3 ligases and discuss their roles and functions.
Highlights
The “guardian of the genome”, p53, has long been known to regulate the cellular responses of DNA repair, cell senescence, cell cycle arrest, and apoptosis [1]
The TA isoforms are able to trigger apoptosis by inducing pro-apoptotic target genes shared with p53, pointing to tumor suppressor function, while the ∆N isoforms can act as dominant negative inhibitors of p53 and the TA isoforms of p63 and p73, suggesting an oncogenic role [23,27,28,29]
It is suggested that mouse double minute 2 (MDM2) and MDMX work together to inhibit p53, at least during embryo development. It is the MDM2–MDMX heterodimer that is essential in suppressing p53 during embryogenesis, rather than MDM2’s E3 ligase activity, and MDM2 E3 ligase activity is dispensable for development [171,174]
Summary
The “guardian of the genome”, p53, has long been known to regulate the cellular responses of DNA repair, cell senescence, cell cycle arrest, and apoptosis [1]. The TA isoforms are able to trigger apoptosis by inducing pro-apoptotic target genes shared with p53, pointing to tumor suppressor function, while the ∆N isoforms can act as dominant negative inhibitors of p53 and the TA isoforms of p63 and p73, suggesting an oncogenic role [23,27,28,29]. TAp73 KO mice have been shown to be more susceptible to spontaneous and stress-induced carcinogenesis [36] As both p63 and p73 have been shown to be prognostic markers for certain types of cancer, the regulation of p63 and p73 and the interplay between its isoforms appear critical in understanding the role of the p53 network in tumorigenesis [23,26]
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