Mutant p53 facilitates somatic cell reprogramming and augments the malignant potential of reprogrammed cells

Abstract

p53 deficiency enhances the efficiency of somatic cell reprogramming to a pluripotent state. As p53 is usually mutated in human tumors and many mutated forms of p53 gain novel activities, we studied the influence of mutant p53 (mut-p53) on somatic cell reprogramming. Our data indicate a novel gain of function (GOF) property for mut-p53, which markedly enhanced the efficiency of the reprogramming process compared with p53 deficiency. Importantly, this novel activity of mut-p53 induced alterations in the characteristics of the reprogrammed cells. Although p53 knockout (KO) cells reprogrammed with only Oct4 and Sox2 maintained their pluripotent capacity in vivo, reprogrammed cells expressing mutant p53 lost this capability and gave rise to malignant tumors. This novel GOF of mut-p53 is not attributed to its effect on proliferation, as both p53 KO and mut-p53 cells displayed similar proliferation rates. In addition, we demonstrate an oncogenic activity of Klf4, as its overexpression in either p53 KO or mut-p53 cells induced aggressive tumors. Overall, our data show that reprogrammed cells with the capacity to differentiate into the three germ layers in vitro can form malignant tumors, suggesting that in genetically unstable cells, such as those in which p53 is mutated, reprogramming may result in the generation of cells with malignant tumor-forming potential.

Mutant p53 Disrupts MCF-10A Cell Polarity in Three-dimensional Culture via Epithelial-to-mesenchymal Transitions

“…Mutant p53 also is found to promote invasion, loss of directionality of migration, and metastatic behavior via increased recycling of integrin (11). In addition, mutant p53 is found to facilitate somatic cell reprogramming and augments the malignant potential of reprogrammed cells (12). A recent study showed that mutant p53 can compete with wild-type p53 to promote epithelial-to-mesenchymal transition (EMT) 2 and regulate the EMT-associated stem cell-like phenotype (13).…”

Mutant p53 is a transcriptional co-factor that binds to G-rich regulatory regions of active genes and generates transcriptional plasticity

“…9 Furthermore, mutp53 strongly enhances reprogramming efficiency and can replace one of the classical reprogramming factors, but the resulting cells are highly tumorigenic. 57 The "epigenetic alteration of transcription" by mutp53 would very likely be intrinsically stochastic due to slight differences in the transcriptional status of single cells. In fact, the observed variability in the gene expression pattern observed upon mutp53 depletion supports such a stochastic model for gene regulation by mutp53.…”

Xenopatients 2.0: Reprogramming the epigenetic landscapes of patient-derived cancer genomes

“…2,3 These and subsequent studies demonstrated that virtually all cell types can generate induced pluripotent stem (iPS) cells when the appropriate reprogramming gene sets are used, which supports the hypothesis that most, if not all, somatic mammalian cells possess dedifferentiation potential and confirms the inherent reversibility of the steps of cellular differentiation. The fact that several reprogramming transcription factors represent bona fide oncogenes, whereas many genes that act as barriers to nuclear reprogramming correspond to known tumor suppressors (e.g., p53), [45][46][47][48][49][50] strongly suggests that the necessary epigenetic rewiring for cellular reprogramming may be partially recapitulated during cellular transformation. Accordingly, the use of an iPS cell expression signature comprised of genes that are consistently upregulated in independent studies with iPS cultures has revealed significant similarities between p53-mutated cancers and cells that have undergone intentional reprogramming in vivo.…”