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

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

p53 Plays a Role in Mesenchymal Differentiation Programs, in a Cell Fate Dependent Manner

Background: The tumor suppressor p53 is an important regulator that controls various cellular networks, including cell differentiation. Interestingly, some studies suggest that p53 facilitates cell differentiation, whereas others claim that it suppresses differentiation. Therefore, it is critical to evaluate whether this inconsistency represents an authentic differential p53 activity manifested in the various differentiation programs. Methodology/Principal Findings: To clarify this important issue, we conducted a comparative study of several mesenchymal differentiation programs. The effects of p53 knockdown or enhanced activity were analyzed in mouse and human mesenchymal cells, representing various stages of several differentiation programs. We found that p53 downregulated the expression of master differentiation-inducing transcription factors, thereby inhibiting osteogenic, adipogenic and smooth muscle differentiation of multiple mesenchymal cell types. In contrast, p53 is essential for skeletal muscle differentiation and osteogenic re-programming of skeletal muscle committed cells. Conclusions: These comparative studies suggest that, depending on the specific cell type and the specific differentiatio

P53-dependent transcriptional regulation of EDA2R and its involvement in chemotherapy-induced hair loss

AbstractThe p53 tumor suppressor coordinates a multitude of cellular and organismal processes and exerts its activities mainly by activation of gene transcription. Here we describe the transcriptional activation of ectodysplasin A2 receptor (EDA2R) by p53 in a variety of cell types and tissues. We demonstrate that treatment of cancer cells with the ligand EDA-A2, known to specifically activate EDA2R, results in p53-dependent cell death. Moreover, we show that EDA2R is transactivated by p53 during chemotherapy-induced hair-loss, although its presence is not necessary for this process. These data shed new light on the role of EDA2R in exerting p53 function