# Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemess
## 1 Introduction  
### The p53 Network and Its Role in Cancer  
Our knowledge of p53 has developed extensively over the past four decades as scientists have unraveled its distinct biological processes. p53 has been associated with several functions in normal cells and cancer. The discoveries by six independent laboratories in 1979 have become the focal point igniting what is now decades of research devoted to p53. These studies found the 53-kDa protein to be bound to Large Tumor Antigen in Simian Virus (SV40) infected tumor cells. In the same period, a separate group identified p53 in transformed but not normal mouse cells from reactions with mouse sarcoma antiserum [1; 2; 3; 4; 5; 6]. Initially, p53 was thought to be an oncogene [7; 8; 6]; however, the consensus in the next decade acknowledged the main function of p53 as a tumor suppressor that is often mutated or nonfunctional in cancer [9; 10; 11; 12; 13]. In contrast to \(mut\)p53, overexpression of \(wt\)p53 halted cell proliferation through control of the cell cycle and induction of apoptosis. In fact, in leukemia cells expression of \(wt\)p53 led to apoptosis confirming the tumor suppressor function of \(wt\)p53 [14; 15; 16; 17]. Dysfunctionalregulation at cell cycle checkpoints that are normally regulated by _wt_p53, are bypassed by damaged cells when p53 is inactivated or mutated leading to uncontrolled growth and carcinogenesis [18,19]. Most of the investigated functions of p53 are associated with full-length p53 (TAp53). Twelve isoforms are encoded in the TP53 gene: TAP53 (\(\alpha\),\(\beta\),\(\gamma\)) \(\Delta\)40p53 (\(\alpha\),\(\beta\),\(\gamma\)), \(\Delta\)133p53 (\(\alpha\),\(\beta\),\(\gamma\)) and \(\Delta\)160p53 (\(\alpha\),\(\beta\),\(\gamma\)) [20, 21, 22, 23]. The transactivation domain is present in long p53 isoforms TAP53 and \(\Delta\)40p53, but not short p53 isoforms \(\Delta\)133p53 and \(\Delta\)160p53. Isoforms \(\beta\) and \(\gamma\) do not contain a canonical C-terminal oligomerization domain, but rather possess an additional domain with unknown function(s) [24]. The most prominent activity associated with p53 is its function as a tumor suppressor. As the \"guardian of the genome\", p53 induces cell cycle arrest, apoptosis, autophagy or senescence in response to DNA damage and other genotoxic insults. p53 restricts cell proliferation to limit the continual propagation of abnormal genomes pillaged by ribonucleotide depletion, nutritional starvation, and hypoxia. Additionally, p53 has been shown to regulate microRNAs, energy metabolism, and anti-oxidant defense [25, 26, 27, 28] (Figure 1). In response to these stress factors, p53 is stabilized through posttranslational modifications via phosphorylation, acetylation, ubiquitination, methylation, neddylation, or SUMOylation [26, 27, 28, 29]. For example, p53 is stabilized by the phosphorylation of the N-terminus at amino acid sites Ser\({}^{15}\), Ser\({}^{20}\), Ser\({}^{33}\), Ser\({}^{37}\), Ser\({}^{46}\), Thr\({}^{18}\) and Th\({}^{81}\), which block the Mdm2 binding to p53. The C-terminus of p53 can be phosphorylated to activate p53 DNA binding activity at Ser\({}^{315}\) and Ser\({}^{392}\). Acetylation at Lys\({}^{320}\), Lys\({}^{373}\) and Lys\({}^{382}\) or SUMOylation at Lys\({}^{386}\) has also been observed in this region [30,31]. Once activated the interactive p53 network seeks to maintain genetic stability and prevent tumorigenesis. Likewise, p53 levels and activity must be tightly controlled to permit the growth and development of normal cells. p53 can upregulate the Mdm2 gene, while elevated levels of p53 can signal Mdm2 downregulation of p53 via ubiquitination and proteosomal degradation maintaining normal p53 steady state levels through a negative feedback loop [32, 33, 34, 35]. Genotoxic stress, such as radiation exposure can increase p53 levels and transcriptional activity resulting in the inhibition of DNA replication to allow for DNA repair or enable cell death processes to prevent the continual propagation of malignant cells.