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 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.

Putting p53 in Context

“…Moreover, one would not presume a priori that the p53 output generated by DNA damage would exactly mirror the gene expression signature elicited by oncogene activation, even in a single cell type. Despite data indicating that p53 can, in principle, control a wide variety of biological processes (reviewed in Olivos and Mayo, 2016), the physiological settings in which one or more processes predominate are incompletely understood and deserve more systematic study.…”

“…In stem and progenitor cells of the hematopoietic system, liver, brain, and breast, p53 restricts cellular self-renewal (Friedmann-Morvinski et al, 2012; Tosoni et al, 2015; Tschaharganeh et al, 2014). Trp53 -null mice consequently have expanded numbers of tissue specific stem cells, highlighting its importance in maintaining tissue homeostasis (Olivos and Mayo, 2016). p53 limits cellular plasticity (governing transition between cell states) and, at its extreme, the ability of somatic cells to undergo epigenetic reprogramming into induced pluripotent stem cells (Olivos and Mayo, 2016).…”

“…Trp53 -null mice consequently have expanded numbers of tissue specific stem cells, highlighting its importance in maintaining tissue homeostasis (Olivos and Mayo, 2016). p53 limits cellular plasticity (governing transition between cell states) and, at its extreme, the ability of somatic cells to undergo epigenetic reprogramming into induced pluripotent stem cells (Olivos and Mayo, 2016). The iPS-promoting factors KLF4 and Oct4 repress p53, and conversely, p53 activity antagonizes the efficiency of iPS cell reprogramming (Menendez et al., 2010).…”

The Emerging Landscape of p53 Isoforms in Physiology, Cancer and Degenerative Diseases

“…In response to a mutagenic or stress stimulus (e.g., nutrient deprivation) or changes in cell signalling and tissue homeostasis, p53 is activated, initiating different adaptive protein expression programs to maintain/restore tissue integrity and biological functions by triggering and coordinating different cell fate decisions in the diverse cell types composing the damaged organs. p53 induces and coordinates cell repair, cell survival, senescence, migration of immune, endothelial and progenitor cells, stem-cell renewal, differentiation and cell death depending on the cell type and function, the active signalling pathways, the type of damage, the cell cycle stage, nutrient availability, the immune response and the presence of pathogens [2][3][4][5][6][7].…”

miR‑125a is upregulated in cancer stem‑like cells derived from TW01 and is responsible for maintaining stemness by inhibiting p53

“…It has also been demonstrated that p53 suppresses the self-renewal and osteogenic differentiation properties, which may be rescued via p53 RNA interference (21). In CSCs, p53 was also determined to regulate the maintenance of stemness (22). Hegde et al (23) determined that, in leukemia stem cells (LSC), overexpression of wild-type p53, but not mutant p53 lacking DNA binding activity, resulted in LSCs gaining properties, such as proliferating and invasive capacities, and losing their self-renewal capacity.…”