Interestingly, most BM progenitors underwent Mutp53LOH

Interestingly, most BM progenitors underwent Mutp53LOH. progenitors exposed that p53LOH is definitely a bi-directional process, which may result in either the loss of wild-type (WT) or Mut p53 allele. Interestingly, most BM progenitors underwent Mutp53LOH. Our results suggest that the bi-directional p53LOH process may function as a cell-fate checkpoint. The loss of Mutp53 may be regarded as a DNA restoration event leading to genome stability. Indeed, gene expression analysis of the p53LOH process exposed upregulation of a specific chromatin remodeler and a burst of DNA restoration genes. However, in the case of loss of WTp53, cells are endowed with uncontrolled growth that promotes malignancy. Heterozygosity, caused by a mutation in one allele of a tumor suppressor gene (TSG), is one of the first methods in malignant transformation.1 Often, TSGs undergo loss of the wild-type (WT) allele, designated as loss Rabbit Polyclonal to FLI1 of heterozygosity (LOH).2, 3, 4 Individuals with the rare tumor predisposition Li-Fraumeni syndrome (LFS), carrying germ-line heterozygous p53 mutations,5 apparently show normal development yet later in adult existence develop a wide spectrum of tumors; predominantly sarcomas,6, 7, 8 where 40C60% of tumors show WT p53 loss of heterozygosity (p53LOH).8 Giving that malignancy development could be associated with stemness deregulation difficulties, the notion the occurrence of p53LOH in stem cells (SCs) may contribute to the emergence of malignancy SCs. Genomic fidelity is definitely a hallmark of SCs.9 The genome of embryonic stem cells (ESCs) is extremely stable, whereas adult stem cells (ASCs) exhibit a less stable genome.10 Genetic deregulation in ASCs was shown to be associated with tumor development.11, 12, 13 Mesenchymal stem cells (MSCs) that acquire mutations in oncogenes/TSGs such as p53 may function as tumor-initiating cells leading to sarcomagensis.14, 15, 16, 17 Furthermore, MSCs isolated from young mice, aged in tradition acquired clinically relevant p53 mutations.18 In all, these findings suggest a link between p53 inactivation in SCs and tumorigenesis. Although induced pluripotent stem cells (iPSCs) seemed to represent ESCs,19, 20 several studies questioned the assumption that iPSCs are as genomically stable as ESCs.21, 22, 23, 24 p53 was found to have a major part in the generation of iPSCs both in attenuating reprogramming and controlling the quality of the reprogrammed cells.25, 26 An additional role of p53 during reprogramming may be an indirect effect on cell proliferation27 and on ATN-161 the restriction of mesenchymalCepithelial transition during the early phases of reprogramming.28 Importantly, Mutp53 cells exhibiting a fully reprogrammed iPSC phenotype SC p53LOH models (iPSCs, MSCs) can help decipher the role of p53LOH in cancer initiation. Indeed, the incidence of p53LOH was found to be extremely different between these SCs. Surprisingly, we found that reprograming of heterozygous p53 (HZp53) fibroblasts, which frequently undergo p53LOH, gave rise to iPSC clones, most of which retained their HZp53 status and exhibited features of normal WTp53-iPSCs. However, p53LOH process is usually strong in MSCs. Interestingly, single-cell sub-cloning of iPSCs, MSCs and bone marrow (BM) progenitors revealed that, in addition to the loss of the WTp53, loss of the Mutp53 allele also takes place. Of notice, this bi-directional p53LOH occurred in an age-dependent manner linking LOH to aging and tumorigenesis. ATN-161 Surprisingly, most of the p53LOH events in BM progenitors favored the loss of the Mutp53 allele. Taken together, our results of a bi-directional p53LOH process, accompanied by a ATN-161 burst of DNA repair pathways, may suggest that p53LOH can be regarded as a DNA repair event. In the case of a DNA repair-orientated productive LOH process, where the Mutp53 allele is usually lost, cells are rescued of tumorigenesis. However, when the WTp53 allele is usually lost, cells become prone to tumor initiation. Results Mouse embryonic fibroblasts (MEFs) undergo p53LOH and found that WTp53-LOH occurred in 100% of examined MEFs at day 12 (passage 7). This correlated with a distinct shift in their proliferation capacity (Figures 1a and b).