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Review
. 2016 Nov 26;17(12):1982.
doi: 10.3390/ijms17121982.

Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness

David J Olivos  1   2 , Lindsey D Mayo  3   4
Affiliations
Review

Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness

David J Olivos et al. Int J Mol Sci. .

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.

Keywords: Mdm2; cancer stem cell (CSC); colonization; mutant p53; niche; non-canonical function; normal stem cells; p53; regulation; survival; translational modifications.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Functions of p53.
Figure 2
Figure 2
p53 functions in normal stem cells at normal conditions and DNA damage.
Figure 3
Figure 3
Role of p53 in cancer stem cells.
Figure 4
Figure 4
Targeting of the p53 Network in cancer stem cells. (A) Restoring p53 transcriptional activity be preventing/restoring p53 exclusion from the nucleus; (B) targeting molecules to disrupt the p53-Mdm2 interaction to prevent p53 degradation; (C) restoring mutant p53 function by modifications; (D) targeting CSC pathways.
See this image and copyright information in PMC

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