Δ40p53 is an embryonic isoform of p53 that controls IGF signaling and stem cell potency
Ungewitter, Erica Kathleen, Department of Cell Biology, University of Virginia
Scrable, Heidi, Department of Cell Biology, University of Virginia
Δ40p53 is an N-terminally truncated isoform of the tumor suppressor p53. Lacking a large portion of the transactivation domain, Δ40p53 itself has minimal transcription factor function. Rather, it forms complexes with and modulates the transcriptional activity of the full-length p53 protein. Ectopic overexpression of Δ40p53 causes p53-dependent progeria and reduced lifespan in mice and impairs the regenerative capacity of adult stem cells. For my thesis research, I chose to investigate the developmental origins of the Δ40p53 progeroid phenotype, using embryonic stem cells (ESCs) as a model system. In the studies presented in this dissertation, I show that Δ40p53, in addition to being highly expressed in ESCs, is the major p53 isoform during early stages of embryogenesis in the mouse. By altering the dose of Δ40p53 in ESCs, I have identified a critical role for this isoform in maintaining the ES cell state. Haploinsufficiency for Δ40p53 causes a loss of pluripotency in ESCs and acquisition of a somatic cell cycle, while increasing the dose of Δ40p53 prolongs pluripotency and inhibits progression to a more differentiated state. ∆40p53 controls the switch from pluripotent ES cell to differentiated somatic cell by regulating the activity of full-length p53, in particular by controlling the insulin-like growth factor receptor (IGF-1R). Based on these data, I propose that the primary function of Δ40p53 may be during the earliest stages of embryogenesis, when it is a critical suppressor of p53 transcriptional activity in cells of the embryo. My findings may also be applicable to the study of Δ40p53 in the processes of adult stem cell renewal, organismal aging, and cancer. I have included lengthy discussions on the role of Δ40p53 in the fields of aging and cancer research in chapters four and five.
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PHD (Doctor of Philosophy)
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