# Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemess
## 5 Discussion  
Stem cells serve an indispensable role in normal development and organ regeneration. Stem cells and progenitors can differentiate into various tissues in the body, repair damaged tissue and serve as a resident population of quiescent cells throughout the life of an organism. However, these cells may undergo neoplastic transformation, leading to dysregulation in normal stem cell processes. Uncontrolled self-renewal and differentiation result in deleterious consequences on development, aging and tumorigenesis. p53 is involved in several distinct processes that influence normal stem cell functions, maintaining stem cell number and quality. Functioning as a guardian between non-malignant stem cells and CSCs, p53 prevents stem cell dedifferentiation and propagation of cells with genomic abnormalities. Many advances have been made in unraveling the mechanisms of cancer progression. The tumor suppressor p53 has been an investigative focal point for nearly four decades. Despite the advances in current cancer therapeutics, advanced tumors continue to evade our most versatile treatments due to the inability to effectively target and eliminate CSCs. It is now evident that a link has been revealed between the concept of \"stemness\" and its regulation by the guardian of the genome, p53, in non-malignant stem cells and CSCs. In order to adequately treat cancer and ensure the success of President [PERSON] and Vice President [PERSON]'s 2016 National Cancer Moonshot Initiative, it is imperative that future studies focus on understanding the mechanisms that maintain stable genomes in stem cells and how these signaling pathways are deregulated in the genesis of CSCs and CSC-mediated tumor recurrence. Studies have revealed similar signaling pathways among non-malignant stem cells and CSCs. The Wnt, Hedgehog, BMI-1, Notch and PTEN evolutionarily-conserved pathways have demonstrated regulatory roles in the self-renewal and the cell fate decision of embryonic and hematopoietic stem and progenitor cell, as well as the maintenance of CSCs. _wt_p53, p53 isomers, _mut_p53 and p53 binding and regulatory factors, such as Mdm2, have been implicated in the stemness regulation processes. Targeting these CSC pathways and their intricate and interactive tumor milieu may prevent tumor recurrence following surgery, chemotherapy and radiation. p53 isomers encompass at least 12 different p53 proteins, and _mut_p53 constitutes a multitude of proteins. Most investigations of _mut_p53 have been explored at mutations in the amino acids 175, 245, 248, 249, 273 and 282 in the DNA binding domain. Likewise, other domains have been found to be mutated, but their contribution to tumorigenesis and stem cell regulation have not been thoroughly investigated [276]. Different tumor types at varying stages of malignancy display a diverse spectrum of _mut_p53 protein function in a variety of oncogenic and stem-conferring processes. The frequency of missense mutations differs in subclasses of tumors of the same organ. This is evident in breast cancers where luminal types mostly exhibit p53 point mutations, whereas basal tumors mostly detect alternations resulting in p53 truncation [277]. Understanding the distinct functions of each form of p53 protein is central to discovering the stemness mechanism that enables CSCs to propagate and interact with specific tumor niches and promote metastasis. Developing novel drug strategies for these p53 targets influencing tumorigenesis and cancer stemness will be challenging and necessitate a critical understanding of the p53, p53 isomers and _mutp_53 upstream and downstream stem pathways and interacting partners, such as PTEN and MDM2. When investigating the processes contributing to stemness, it is vital to understand which factors come into play. The frequencies of CSCs were once believed to be as rare as 0.0001% to 0.1% of all cancer cells [79; 85].