The Role of the p53 Protein in Stem-Cell Biology and Epigenetic Regulation

Abstract

The p53 protein plays a passive and an active role in stem cells. The transcriptional activities of p53 for cell-cycle arrest and DNA repair are largely turned off in stem cells, but there is some indication that long-term stem-cell viability may require other p53-regulated functions. When p53 is activated in stem cells, it stops cell division and promotes the commitment to a differentiation pathway and the formation of progenitor cells. In the absence of any p53 activity, stem-cell replication continues and mistakes in the normal epigenetic pathway occur at a higher probability. In the presence of a functionally active p53 protein, epigenetic stability is enforced and stem-cell replication is regulated by commitment to differentiation. Over a lifetime of an organism, stem-cell clones compete in a tissue niche for Darwinian replicative advantages and in doing so accumulate mutations that permit stem-cell replication. Mutations in the p53 gene give stem cells this advantage, increase the clonal stem-cell population, and lower the age at which cancers can occur. Li-Fraumeni patients that inherit p53 mutations develop tumors in a tissue-type-specific fashion at younger ages. Throughout the life of a Li-Fraumeni patient, the tumor types that arise occur in tissues where stem cells are active and cell division is most rapid. Thus, p53 mutations that are inherited or occur during developmental life act in stem cells of the mesenchymal and epithelial lineages, whereas p53 mutations that occur in progenitor or differentiated (somatic) cells later in life function in tissues of endodermal origins, indicating that p53 may function differently in different developmental lineages.

The Roles of Initiating Truncal Mutations in Human Cancers: The Order of Mutations and Tumor Cell Type Matters

“…These results were also consistent with the fact that individuals that inherited an APC mutation developed colorectal tumors at earlier times and greater frequencies than individuals with spontaneous mutations in APC (Kinzler and Vogelstein, 1996). They were also consistent with studies showing that individuals that inherit TP53 mutations, rarely, if ever, develop CRCs over their lifetime, but do develop lots of other tumor tissue types (Levine et al, 2016).…”

“…These results were also consistent with the fact that individuals that inherited an APC mutation developed colorectal tumors at earlier times and greater frequencies than individuals with spontaneous mutations in APC (Kinzler and Vogelstein, 1996). They were also consistent with studies showing that individuals that inherit TP53 mutations, rarely, if ever, develop CRCs over their lifetime, but do develop lots of other tumor tissue types (Levine et al, 2016).Until fairly recently it was generally assumed that cancer evolves through a linear stepwise selection of genetic changes. This thinking was radically altered in 2012 when Gerlinger et al (2012) showed that clear-cell renal carcinoma evolved through branching tumor evolution, similar to Darwin's iconic evolutionary tree.…”

“…Second, by selecting for mutations in four distinct signaling pathways (WNT, RAS, TGF-b [SMAD4], and p53), four different functional aspects of tumor development, including metabolic processes and the cell cycle, the extracellular matrix and signaling, and genomic instability, were all altered, but in a specific order and sets of combinations. This hypothesis, that the order in which cancer driver mutations develop in a cell can influence the timing and phenotype of a tumor, helps to explain why an inherited APC mutation commonly results in a CRC, but an inherited TP53 mutation does not, even though 93% of individuals with TP53 mutations will develop 1 to 20 tumors over their lifetime (Levine et al, 2016).Rather clear proof that the order of addition of the four major mutations driving CRC is important for the timing of CRC development was confirmed using mouse models (Takeda et al, 2015). These models used Sleeping Beauty (SB) transposonbased insertional mutagenesis to induce gastrointestinal (GI) tract tumors in wild-type mice, or mice that carried heterozygous inactivating mutations in Apc, Smad4 (to activate TGF-b signaling), or Trp53, or an activating mutation in Kras.…”

microRNA: The Impact on Cancer Stemness and Therapeutic Resistance

“…All three are tumor suppressors. In stem cells, the presence of p53 stops cell differentiation and promotes the conversion of stem cells to progenitor cells [111]. PTEN suppresses the PI3K/Akt pathway to inhibit cell differentiation and induce cell death [112].…”

Role of Epigenetic Regulation of Growth Arrest States in Normal and Cancer Cells

“…By contrast, there is a vast literature on the epigenetic control of mammalian cell senescence in both normal and cancer cells by cell cycle dependent histone deacetylase inhibitors in fibroblast cells [18]. Many reports involve the role of p53 tumor suppressor gene activation and high levels of p16 as mediated thru MEK/MAPK mitogenic signaling [19][20][21][22][23] Other epigenetic mechanism involve the over expression of ectopic RAS [24], telomere shortening [25], and finally, the role of WNT16B in human epidermal keratinocyte proliferation control [26]. What about reversible G 1 cell cycle arrest?…”