title: Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness.
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 whichwtp53 andmutp53 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.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. djolivos@iupui.edu.|Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. djolivos@iupui.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Olivos
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. ldmayo@iu.edu.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. ldmayo@iu.edu.
authors.forename: Lindsey D
authors.initials: LD
authors.lastname: Mayo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Mdm2; cancer stem cell (CSC); colonization; mutant p53; niche; non-canonical function; normal stem cells; p53; regulation; survival; translational modifications