# 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 response to genotoxic stress, the tumor suppressor p53 induces transient growth arrest or apoptosis and mediates a cellular process of limited proliferation and irreversible growth referred to as senescence and the cell cycle G1/S checkpoint. p53 isoforms have also been implicated in replicative senescence and, similar to _wt_p53, participate in cell cycle progression, angiogenesis, programmed cell death, viral duplication and cell differentiation [205; 206; 207; 208; 209; 210]. Cells with significant DNA damage undergo p53-dependent apoptosis [211]. [PERSON] et al. (1997) [212] demonstrated that _wt_p53 triggers senescence in human tumor cells lacking functional p53. Dividing and proliferating cells frequently experience more DNA double-strand break damage than do non-proliferating cells [213; 214]. mESCs do not experience p53-dependent apoptosis at the G1/S checkpoint after DNA double-strand break damage and, therefore, do not experience cell cycle arrest, apoptosis and senescence. p53 can suppress the ESC self-renewal and pluripotency after DNA damage [215]. p53\({}^{-/-}\) hESCs have been used to show that the role of p53 in suppressing pluripotency is conserved in mouse and human ESCs. In MEFs, [PERSON] et al. (2002) reported that oncogenic _ns_ and p53 cooperate to induce senescence through activation of the MAP kinase pathway [216]. [PERSON] et al. (2011) [217] showed that mice lacking Mdm2 in the epidermis activate p53 signaling in the epidermal stem cell to promote senescence and premature aging phenotypes in mouse skin as characterized by thinning of the epidermis, reduced wound healing and progressive loss of fur. Contemporary chemotherapies can obliterate the majority of dividing and proliferative cancer cells in the tumor; however, the inability to completely eradicate CSCs ensures tumor recurrence (Figure 3). CSCs have been shown to acquire resistance mechanisms, such as DNA repair, drug efflux, ATP-binding cassette (ABC) transporters, detoxifying agents, anti-apoptotic agents, morphological changes and quiescence [218; 219; 220]. Quiescence or slow cell cycling is a feature shared among non-malignant stem cells and CSCs involved in self-renewal and preventing stem cell exhaustion. Quiescence is a reversible process that can be restored by stimulation with the addition of growth factors to resume proliferation. HSCs likely use quiescence to maintain the HSC self-renewal compartment for the lifetime of the organism to sustain and give rise to all hematopoietic lineage cells [221; 222; 223; 224]. Quiescence also protects dormant stem cells from various stresses, such as myelosuppression induced by 5-fluorouracilacil (SFU)-treatment. Similarly, CSC are able to avoid the effects of chemotherapy by acquired resistance [221]. In hair follicle stem cells (HFSCs), the state of quiescence is a form of tumor suppression. Cancer cells originating from HFSCs give rise to cutaneous squamous cell carcinoma. Tumorigenesis is averted when the cell cycle is stalled at G0/G1, suggesting that the processes maintaining HFSCs' dormancy are dominant over oncogene gain (i.e., Ras) or p53 tumor suppressor loss. Many intrinsic mechanisms known to regulate quiescence include transcription factors FoxO, HIF-1\(\alpha\) and NFATc1, and signaling through ATM and mTOR. Multiple extrinsic regulatory mechanisms in the microenvironment have been identified, including bone morphogenic protein (BMP), osteopontin, thrombopoieetin (TPO), angiopoietin-1 (Ang-1), tumor growth factor-\(\beta\) (TGF-\(\beta\)), N-cadherin and integrins, as well as Wnt/\(\beta\)-catenin signaling [225]. PTEN is an alternative factor that contributes to the maintenance of quiescence in the presence of tumorigenic stimuli preventing tumorigenesis [226]. PTEN also plays an important role in sustaining p53 levels in tumor cells, which may concomitantly regulate stem cell quiescence.