# Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemess
## 2 p53 and Stem Cells
p53 can suppress the epithelial-mesenchymal transition (EMT), an activator of stemness and cell motility phenotype, and activate miR-200c expression, which suppresses EMT-activators, ZEB factors and translational stem cell factors (e.g., BMI-1, Nanog, Sox2) to induce mesenchymal-epithelial-translation (MET) [152; 153; 154; 155]. In fact, miR-200 family members are downregulated in breast CSCs and breast epithelial stem cells [157]. _Mut_p53 GOF induces EMT transition by modulating the miR-130b-ZEB axis in endometrial cancer [158]. These emerging links between p53 and stem cell homeostasis and pluripotency enabled [PERSON] et al. (2015) [24] to propose that p53 be considered the \"guardian of reprogramming\" in addition to its recognized role in the genome. Like p53 mutants, p53 isoforms have also been implicated in promoting CSC potential. Overexpression of the p53 isoform p53\(\Lambda\)133p53\(\beta\) promotes stemness in MCF-7 breast CSCs by regulating the expression of stem cell factors Sox2, Oct3/4, Nanog and CD24/CD44 and promotingmammosphere formation [24]. Furthermore, \(\Delta\)133p538 induction through etoposide treatment enhances cancer cell stemness. [PERSON] et al. (2015) [159] showed that p53 isoform \(\Delta\)113p53/\(\Delta\)133p53 promotes DNA double-strand break repair to protect cells from death and senescence in response to DNA damage. p53 maintains ESC genetic stability as a DNA damage repair response by inducing differentiation. Disrupting or inactivating of p53 increases pluripotent stem cell production [146]. p53\({}^{-/-}\) iPSCs exposed to DNA damage, carry short telomeres and chromosome aberrations and are genetically unstable [138]. By decreasing p53 levels in mouse fibroblasts, [PERSON] et al. (2009) demonstrated that two critical transcripts, Oct-4 and Sox2, increase iPSC production [137]. p21, a known p53 target, was also found to be a main player in p53-directed reprogramming and generation of iPSCs. [PERSON] and [PERSON] (2010) [160] showed that \(\Delta\)40p53, a transactivation-deficient isoform of p53 that is highly expressed in ESCs and during early stages of mouse embryogenesis, controls the switch from pluripotent ESCs to differentiated somatic cells. \(\Delta\)40p53 acts as a master regulator of this pluripotency switch via IGF and PI3K signaling by controlling IGF-1 receptor (IGF-1R) levels and the activity of full-length p53 with Nanog and IGF-1R. Accumulating evidence has linked _wtp_53, _mut_p53 and p53 isomers to stemness in both non-malignant stem cells, such as ESCs, iPSCs and tumor CSCs. It is becoming increasingly evident that p53 may possess a stemness role in non-malignant and CSCs beyond its main tumor suppressor function. p53 suppresses self-renewal and induces differentiation in embryonic development and organogenesis. In response to DNA damage, mouse ESCs (mESCs) activate p53 to bind to the promoters of self-renewal and pluripotency genes Nanog and Oct4, evoking differentiation into cell states responsive to p53-induced cell cycle arrest or apoptosis [106; 161; 107]. Activation of p53 through Oct4 silencing promotes human ESC (hESC) differentiation due to the repression of the p53 inhibitor Sirt1 and acetylation of p53 at lysine 120 and 164 [162]. Understanding how the mechanisms of p53 stemness function in normal and malignant cells may reveal novel targets for therapeutic intervention. Aggressive tumors with stem-like phenotypes may be prone to manipulation by directing differentiation into responsive cell types. Targeting self-renewal signaling pathways or cell surface markers could also be implemented to eradicate CSCs. Furthermore, restoration of _wtp_53 and inhibition of _mut_p53 and CSC-associated p53 isomers might lead to the reduction of drug resistance and enhance treatment efficacy (Figure 2).