Abstract
Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution of p53 detailing the significant discoveries of each decade since its first report in 1979. In this review, we will highlight the emerging non-canonical functions and regulation of p53 in stem cells. We will focus on general themes shared among p53’s functions in non-malignant stem cells and cancer stem-like cells (CSCs) and the influence of p53 on the microenvironment and CSC niche. We will also examine p53 gain of function (GOF) roles in stemness. Mutant p53 (mutp53) GOFs that lead to survival, drug resistance and colonization are reviewed in the context of the acquisition of advantageous transformation processes, such as differentiation and dedifferentiation, epithelial-to-mesenchymal transition (EMT) and stem cell senescence and quiescence. Finally, we will conclude with therapeutic strategies that restore wild-type p53 (wtp53) function in cancer and CSCs, including RING finger E3 ligases and CSC maintenance. The mechanisms by which wtp53 and mutp53 influence stemness in non-malignant stem cells and CSCs or tumor-initiating cells (TICs) are poorly understood thus far. Further elucidation of p53’s effects on stemness could lead to novel therapeutic strategies in cancer research.
Highlights
Tumor-associated mutp53 acquires gain-of-function (GOF) oncogenic properties that are independent of wtp53
The findings demonstrate that mutp53 tumorigenesis requires secreted interleukin-1 receptor antagonist (sIL-1Ra) suppression, resulting in a chronic pro-inflammatory tumor microenvironment. mutp53 influences tumor and microenvironment interactions and may induce pro-oncogenic gain of function (GOF) changes in tumors and stromal cells alike
These findings demonstrate the potential of the microenvironment to drive and maintain tumorigenesis, including cancer stem-like cells (CSCs)
Summary
Our knowledge of p53 has developed extensively over the past four decades as scientists have unraveled its distinct biological processes. p53 has been associated with several functions in normal cells and cancer. P53 has been associated with several functions in normal cells and cancer. TTohpehseosppohsot-rtyrlaantisolantioofnpa5l 3 maonddifiMcadtmio2n.s Tinhteesrefepreoswt-ittrhanthsleatfioornmalatmioondoifficthateiopn5s3-iMntedrmfe2recowmitphletxherefsourlmtinagtioinn po5f3thsteabpi5li3z-aMtidomn, inccormeapsleedxpr5e3supltriontgeininlepv5e3lssatanbdilitzraantisocnr,ipinticorneaalseadctipv5it3y,parnodteianctlievvaetilosnanodf cterlalncsyccrliepatirornesatl, ascetnivesitcye,nacen,d DaNctAivraetpioaniroafncdelalpcoypclteosairsre[1s9t,,2s5en,3e6s]c.ence, DNA repair and apoptosis [19,25,36] In another example of p53 regulation through a negative feedback loop, ubiquitin ligases Cop and Pirh associate with p53 before undergoing ubiquitination and proteosomal degradation [37,38]. Tumor-associated mutp acquires gain-of-function (GOF) oncogenic properties that are independent of wtp. Tumor-associated mutp acquires gain-of-function (GOF) oncogenic properties that are independent of wtp53 These mutations enable cancer-associated mutp with new properties that benefit the tumor at various levels of cancer progression. The p53 family includes p63 and p73, which share similar gene structures and overlapping, but distinct functions cover a wide range of processes involved in development, apoptosis and cell cycle arrest, chemosensitivity and immortalization [31]. The tumor suppressors p53, p63 and p73 regulate miRNAs that are critical to tumor inhibition and downregulation of EMT, metastasis, and the proliferation of CSCs [68]
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