# Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemess
## 3 p53 Gain of Function Roles in Stemness
### p53 and Stem Cell Senescence and Quiescence
In U87 MG glioblastoma, PTEN protected p53 through inhibition of phosphophatidylinositol 3-kinase (PI3K)/Akt signaling (activation known to promote Mdm2 translocation into the nucleus), resulting in Mdm2 restriction to the cytoplasm, where it is degraded. As a result, p53 levels and transactivation increase, sensitizing U87 MG glioblastoma cells to DNA damage and p53-mediated cell death induced by the chemotherapeutic agent etoposide [41]. Furthermore, the PTEN gene is a transcriptional target of p53, and p53 selectively targets PTEN over  
Figure 3: Role of p53 in cancer stem cells. the Mdm2 gene in cells with sustained genotoxic stress [41]. Though not explored in these studies, it is possible that a chemotherapy response could regulate the PTEN-p53 axis and CSC quiescence. p53 is essential for restraining cell cycle entry. Many studies have associated p53 with regulation of stem cell quiescence. Loss of p53 in neural stem cells (NSCs) and HSCs stem cell expansion, as these cells exit quiescence and progress through the cell cycle [227; 228]. Furthermore, [PERSON] et al. (2013) [229] demonstrated that conditional deletion of Cdkn1a, a p53 target gene encoding cyclin-dependent kinase inhibitor p21, leads to NSC and HSC stem cell proliferation and exhaustion. [PERSON] et al. (2009) [230] showed that p53 regulates HSC quiescence and enhanced quiescence in HSCs lacking the MEF/Elf4 transcription factor, which is known to regulate both HSC self-renewal and quiescence. HSCs transcriptional profiling of _wt_p53 and p53 null mice revealed Gfi-1 and Necdin to be p53 target genes. Gfi-1 maintains HSC functional integrity and inhibits HSC proliferation, while Necdin is a negative cell cycle regulator increasing quiescence. [PERSON] et al. (2002) [227] reported that p53 contributes to a reversible, growth factor-dependent arrest of quiescence (G0) in normal WI-38 human fibroblasts. To abrogate p53 function, fibroblasts were microinjected with Mdm2 or the pRb binding mutant of SVT antigen plasmid DNA, which stimulated quiescent fibroblasts to initiate DNA synthesis. p53 activity was higher in quiescent and senescent fibroblasts compared to actively-proliferating cells when analyzed by electrophoretic mobility shift and p53 transactivation. Growth factor withdrawal from proliferating cells led to G0 arrest, elevated mRNA levels and accumulation of p53, followed by an increase in p21 mRNA and protein expression. p21 is a p53 target gene and effector of cell cycle arrest. Furthermore, stable expression of p53 inhibitors HPVV16 E6 oncogene and dominant negative p53 peptide (GSE-22) delayed entry into G0 after growth factor withdrawal [227]. [PERSON] and [PERSON] (2016) [231] described the polycomb like 1 (PCL1)-p53 regulatory axis as important for the maintenance of cellular quiescence. During development and differentiation, the chromatin-associated transcriptional repressor polycomb proteins maintain cellular identity. The PCL1 gene promoter is a direct transcriptional target of p53 with the N-terminal PHD domain of PCL1 protein binding to the C-terminal regulatory domain (CTD). This interaction stabilizes p53 and activates CDKN1A to promote quiescence [229; 232].