# Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemess
## 3 p53 Gain of Function Roles in Stemness  
### Differentiation and Dedifferentiation  
Studies have confirmed that p53 regulation of stem cell differentiation processes is critical in preventing malignant transformation. Studies showcasing p53\({}^{-/-}\) human ESCs have  
Figure 2: p53 functions in normal stem cells at normal conditions and DNA damage.  
confirmed the suppressive role of p53 in regulating hESC pluripotency and maintaining genomic stability [78; 80; 81; 163]. p53 suppresses self-renewal of ESCs in response to DNA damage [164]. In experiments by [PERSON] et al. (2005), p53 suppresses Nanog expression following DNA damage inducing mESC differentiation during oncogenic stress to inhibit cell proliferation [107]. Using hESCs, [PERSON] et al. (2008) [165] demonstrated that Nutlin, a small molecule inhibitor that binds to the p53 antagonist Mdm2, activated p53 to promote cell differentiation and degradation of cyclins A and E, dephosphorylation of the activating phosphorylation site of CD2 Thr-160, elimination of S phase entry into the cell cycle and activation of p21.  
In cancer, loss of p53 tumor suppressor function often accompanies _mut_p53 GOFs, which enhances tumorigenesis, metastasis, drug resistance, genomic instability and multinucleation [166; 167; 168; 169; 170; 171; 172; 173; 174]. _wt_p53 loss has been associated with enhancing the efficiency of somatic cell reprogramming to a pluripotent state and stem-like phenotype in cancer. [PERSON] et al. (2010) [175] reported that inactivation of p53 in breast cancers and mutations in p53 correlated with stem cell phenotype. [PERSON] et al. (2010) [20] reported that _mut_p53 facilitated somatic cell reprogramming and augmented the malignant potential of reprogrammed cells. Likewise, [PERSON] et al. (2014) [176] found that _mut_p53-R248W/P72R exhibited GOF activity in 3 AB-OS MG63 osteosarcoma cells with its ectopic expression promoting aggressiveness, chemoresistance and cancer stemness. While investigating tumor progression in epithelia ovarian cancer, [PERSON] et al. (2016) [177] reported _mut_p53 regulation of tumor differentiation and responsiveness to steroids. Furthermore, [PERSON] et al. (2013) [178] demonstrated a _mut_p53 R175H GOF in programming mammary tumorigenesis by expanding mammary epithelial stem cells (MESCs) that generate tumors. However, the molecular mechanisms for how p53 promotes stemness and whether the stem-like cells acquire survival advantages for tumor initiation and progression are not clearly understood [174].  
Oxidative stress activates p53 during tissue injury hypoxia resulting in death and differentiation of hESCs. However, hESCs are able to avoid this fate by exerting a cytoprotective effect. [PERSON] et al. (2012) reported conditional reprogramming activity or \"enhanced stemness\" by elevating HIF2\(\alpha\) transcriptional activity in SSEA3\({}^{+}\)/ ABCG2\({}^{+}\) hESCs through transient suppression of p53 activity. The enhanced stemness was transient; however, it provided a highly cytoprotective state with enhanced transcriptional activity of Oct-4 and Nanog in undifferentiated cells. The hESCs also demonstrated high Bcl-2, fibroblast growth factor 2 (FGF2), altering the oscillation system state of p53/Mdm2 [179]. [PERSON] et al. (2016) [180] showed in hESCs that histone modifications and p53 binding enable p21 promoter activation. hESCs' high proliferation rate is due to low expression of p21. p53 binds to the p21 promoter of hESCs, but does not promote p21 transcription in hESCs, as it does in differentiated human mesenchymal stem cells (hMSCs). Enrichment of repressive and activating histone H3K27 me3 at the p21 locus in hESCs overrides activation by p53. Therefore, H3K27 me3 methylation rescues p21 expression while p21 ectopic expression induces hESC differentiation. Epigenetic signals to hESCs prevent undesired p53 target genes from initiating differentiation and maintain genomic stability and homeostasis.