# Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemess
## 3 p53 Gain of Function Roles in Stemness
### Epithelial-Mesenchymal Transition and Stemness  
EMT is a reversible process in which polarized epithelial cells lose their cell-cell adhesions and acquire a spindle-like morphology. The accompanying mesenchymal properties enable cells to migrate and invade distant tissues. This process is essential for gastrulation, neural crest delamination of vertebrates, tissue formation, embryonic cell development, wound healing, fibrosis, carcinogenesis and metastasis [181; 182; 183]. To initiate metastasis, cancer cells activate EMT through environmental signals inducing the expression of SNAIL, TWIST, ZEB1/2, SLUG, SMUC, bHLH factor E47 and BMI-1 transcription factors that interact with epigenetic regulators. Many of these transcription factors target the CDH1 gene, which encodes a fundamental EMT protein, E-cadherin. This trans-differentiation program is driven by a complex network of protein and gene regulation including N-cadherin and _vimentin_ induction, cytoskeletal changes, cell adhesion and ECM degradation [184; 185; 186]. Studies associated the induction of EMT to acquire CSC molecular and functional traits [186; 187]. In immortalized or transformed human mammary epithelial cells, the overexpression of TWIST,ZEB1 or SNAIL converts the cells from a differentiated profile (CD44 low/CD24 high) to a breast CSC signature (CD44\({}^{+}\)/CD24\({}^{-/\mathrm{low}}\)), enabling tumorsphere formation [141; 186; 188]. Inhibition of p53 combined with mitogenic oncoproteins, serving as EMT-inducing factors, drives tumorigenesis, cancer stemness and cell plasticity. [PERSON] et al. (2011) associated p53 activity with stemness modulation in embryonic and undifferentiated cells [174]. During embryogenesis, p53 maintains embryonic cell proliferation and preserves stemness [189; 190]. [PERSON] et al. (2009) [191] demonstrated that p53 was able to regulate the polarity of self-renewing divisions in mammary stem cells. Loss of p53 increased CSC symmetrical divisions, mammosphere formation, tumor initiation and tumor growth. Suppression of p53 inhibits stem cell self-renewal and the reprogramming quality of differentiated cells into iPSCs [107; 192; 193; 194]. In cancer, p53 inactivation is associated with EMT and cancer stemness [174; 175; 195]. TWIST1 is upregulated in a _mut_p53 background promoting the induction of SLUG expression [196; 197].  
[PERSON] et al. (2011) [152] showed that p53 can regulate EMT and stem cell properties by modulating miRNAs. This study found that p53 transactivated miR-200c by directly binding to the miR-200c promoter. Loss of p53 in mammary epithelial cells decreased miR-200c expression to activate EMT and increased mammary stem cell numbers. _wt_p53 directly activates transcription of miR-200 and miR-34 gene loci, creating reciprocal feedback loops to reduce EMT inducers ZEB1 and SNAIL [198; 199; 200]. miR-200 and miR-34 directly inhibit the translation of stem cell factors BMI1, CD44 and CD133 [157; 201; 202]. p53 can also activate miR-145 expression to repress stem cell factors Oct4, KLF4, LIN28A and Sox2 [203]. [PERSON] et al. (2008) [156] reported that miR-200 and miR-194/192 repress ZEB1/2 expression to negatively regulate EMT and metastasis. _wt_p53 directly activates the miR-200c and miR-192 transcription leading to ZEB1/2 downregulation and EMT repression [200]. _Mut_p53 promotes EMT and tumor aggressive potential by inhibiting _wt_p53-miR-200c pathways via dominant-negative effects on _wt_p53 [152]. [PERSON] et al. (2013) [158] demonstrated that a _mut_p53 GOF facilitates EMT and cancer cell invasion through repression of the ZEB1 inhibitor, miR-130b. [PERSON] et al. (2014) [204] reported that p53-induced miR-15a/16-1 and AP4 form a double-negative feedback loop to regulate EMT and metastasis in colorectal cancer. These findings support the role of p53 to function in cellular plasticity, EMT and stemness via regulation of miR-200, miR-34, miR-145 and miR-15a/16.