Study the role(s) of p53 in embryonic stem cells

Division Of Basic Sciences - Nci

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Abstract

During fiscal year (FY) of 2013, we have made significant progress of studying the p53 signaling in embryonic stem cells. 1) We have previously mapped a global p53 signaling in ES cells (Li M, et al., Molecular Cell, 2012). However, it is unknown how the p53 signaling in ES cells is different from that in mouse embryonic fibroblast (MEF) cells. In FY2013, we have addressed this question by comparing and contrasting the p53 signaling in ES cells with that in MEF cells on a genome-wide scale. We are now further investigating the gene sets that are specifically regulated by p53 in ES cells, and hoping to dissect the developmental role of p53 from its tumor suppressive role. 2) In addition to the genome-wide study, we are also performing complementary studies on individual genes. Paradoxically, p53 not only kills but also promotes the survival of tumor cells. This dual function of p53 is mediated by individual genes regulated by p53 upon DNA damage. In FY2013, we focused on a novel p53 target, Rap2b, and found that it plays an important role in the pro-survival after DNA damage. We found that Rap2b is one of the genes that help tumor cells survive after DNA damage. The inhibition of Rap2b sensitizes tumor cells to Adriamycin, a chemotherapy agent. Therefore, studies on individual genes in the p53 signaling have the potential of discovering novel therapeutic targets for cancer treatment and maximizing the tumor-killing effect of chemotherapy. 3) Only 2 percentage of the genome expresses protein-coding transcripts; the rest actively expresses non-coding RNAs, which play important roles in various biological processes. However, the roles of these non-coding RNAs in ES cells are largely unexplored. We hypothesize that noncoding RNAs partially mediate the function of p53 in ES cells. During FY2013, we have identified several long non-coding RNAs (lncRs) that may be involved in p53 signaling in ES cells. Some of these lncRs interact with chromatin-binding protein. We are currently studying the roles of these lncRs in ES cells with a focus on differentiation regulation. This study could broaden our understanding of the biological function of p53 in ES cells. 4) Human ES (hES) cells are a complementary model to mouse ES cells. In the previous fiscal year, we have obtained two human ES cell lines from the Stem Cell Facility at the University of Connecticut. These two hES cell lines are NIH-approved hES cell lines that can be studied using federal funding. In FY2013, we have established a fruitful collaboration with Dr. Guokai Chen's stem cell facility at the National Heart, Lung, and Blood Institute (NHLBI) to generate p53 knockout human ES cells. Dr. Chen was trained with Dr. James Thompson, the pioneer of hES cell study, at the University of Wisconsin, and he is now the head of the stem cell facility at NHLBI. We will study p53 signaling in human ES cells using these two hES cell lines and the p53 knockout hES cell lines. Then, we will compare the p53 signaling in mouse ES cells to that in hES cells and derive a conserved transcriptional network commanded by p53.