# Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemess
## 2 p53 and Stem Cells  
Recent studies have implicated p53 in stem cell plasticity in the areas of self-renewal, differentiation and reprogramming and have associated these processes with tumor cell heterogeneity and progression. For example, focal adhesion kinase (FAK), p53 and Nanog have been found to be interlinked and to cross-regulate CSCs. FAK binds to Mdm2 and activates p53 degradation, whereas p53 upregulation inhibits Nanog and FAK survival signaling pathways, increasing CSC maintenance, cell growth and tumor inhibition [109]. Loss of p53 can induce Hedgehog signaling, upregulating Nanog in glial stem cells and CSCs. [PERSON] et al. (2010) [142] demonstrated that perturbing Hedgehog signaling alters the fate of Nanog to regulate self-renewal associated with glioma stem cell fate and the transforming cell properties of CSCs. p53 binds to the Nanog promoter, repressing its expression in conjunction with the co-repressor mSin3a. p53 is critical to pluripotent cell reprogramming and stem cell renewal [143]. In animal experiments performed by [PERSON] et al. (2011), murine p53\({}^{-/-}\) astrocytes are de-differentiated into CSC-like cells while maintaining neural stem and progenitor phenotypes and self-renewing activities, undergo neuroscience formation in vitro and form tumors in vivo [144]. Increasing evidence suggests that these diverse _mut_p53 GOF processes occur through multiple pathways. [PERSON] et al. (2014) demonstrated that _mut_p53 GOF causes differentiation of human osteosarcoma MG-63 cells into 3 AB-OS CSCs. They investigated the expression of _wt_p53 in 3 AB-OS CSCs compared with parental MG-63 cells. Parental cells contain a single copy of _wt_p53 gene, and the promoter is methylated. 3 AB-OS cells contain a rearranged TP53 gene of multiple copies by the P72R polymorphism and hot spot mutation R248W. Ectopic expression of p53-R248W/P72R lends to a cancer a stem-like phenotype, possessing a high proliferative rate with clonogenic growth, undergoes sphere formation and exhibits strong features of invasiveness and migration. Stem cells and p53 have been associated with Wnt/\(\beta\)catenin signaling pathways, Sonic Hedgehog (Shh), BMI-1 (B-cell-specific Moloney murine leukemia virus insertion site 1), Notch and PTEN pathways that provide a delicate balance of self-renewal and differentiation through niche signaling and the interplay among these pathways [97; 126; 145]. When these signaling pathways become deregulated, the uncontrolled self-renewal capacity of CSCs is presented. Accumulating evidence demonstrates that p53 loss can lead to an acquisition of stemness in cancer, highlighting the role of _wt_p53 and _mut_p53 in non-malignant somatic stem cells and CSCs. Recognizing the similarities between ontogeny and oncology, p53 deficiency and stemness may collectively contribute to tumor initiation and recurrence through survival advantages, such as: disruptions in cell death programming, drug resistance and self-renewal. In non-malignant cells, it has been shown that p53 can influence stem cell homeostasis and pluripotency. _wt_p53 has been observed to counteract somatic cell reprogramming and constrain iPSC generation in vivo [137; 138; 146; 147; 148; 149; 150]. A reduction in p53 increases cell reprogramming efficacy and facilitates induced pluripotent stem cell (iPSC) generation [137]. p53 may also act to regulate stem cell fate by targeting a variety of factors, such as Wig1, a transcriptional p53 target encoding a zinc-finger protein involved in post-transcriptional gene regulation, and is found to be highly expressed in stem cells [151]. In tumors, _mut_p53 acquires GOF processes to influence stemness as observed in its ability to stimulate iPSC formation while augmenting the malignant potential of reprogrammed cells [20].