Abstract
Remarkably, the p53 transcription factor, referred to as “the guardian of the genome”, is not essential for mammalian development. Moreover, efforts to identify p53-dependent developmental events have produced contradictory conclusions. Given the importance of pluripotent stem cells as models of mammalian development, and their applications in regenerative medicine and disease, resolving these conflicts is essential. Here we attempt to reconcile disparate data into justifiable conclusions predicated on reports that p53-dependent transcription is first detected in late mouse blastocysts, that p53 activity first becomes potentially lethal during gastrulation, and that apoptosis does not depend on p53. Furthermore, p53 does not regulate expression of genes required for pluripotency in embryonic stem cells (ESCs); it contributes to ESC genomic stability and differentiation. Depending on conditions, p53 accelerates initiation of apoptosis in ESCs in response to DNA damage, but cell cycle arrest as well as the rate and extent of apoptosis in ESCs are p53-independent. In embryonic fibroblasts, p53 induces cell cycle arrest to allow repair of DNA damage, and cell senescence to prevent proliferation of cells with extensive damage.
Highlights
National Institute of Child Health and Human Development, Bethesda, MD 20892, USA; National Human Genome Research Institute, Bethesda, MD 20892, USA
DNA damage begins to accumulate in Mdm2-/- blastocysts, but less so in embryos that are null for both Mdm2 and the p53-dependent pro-apoptotic gene Bax, suggesting that unregulated p53 can initiate apoptosis in blastocysts that is not lethal until gastrulation [73]
Evidence for p53-dependent transcription first appears during mouse development in the inner cell mass of late blastocysts, and the p53-specific regulatory protein MDM2 first becomes essential for mouse development when gastrulation begins by preventing p53 activity from arresting embryonic development (Sections 4.1 and 4.2)
Summary
P53 is referred to as “the guardian of the genome”, because it maintains genomic stability by arresting proliferation of cells with damaged DNA, minimizing the risk of tumor development by maintaining a pool of healthy cells [1]. Cates that p53 has a role in enabling cells to adjust their metabolism in response to These include maintaining genomic stability by inducing cell cycle arrest, apoptosis or changes in glucose other nutrient levels,and oxygen availability, reactivepluripotency oxygen spesenescence [19,20,21],and regulating homeostasis metabolism [22], and regulating cies differentiation [29,30]. Of theand approximately human protein coding [33] These high-confidence apoptosis senescence,000 whereas milder stress leadsgenes to a transient growth arrest coup target genes function in multiple processes. Severe stress induces apoptosis and senescence, whereas milder stress leads to a transient growth arrest coupled with an attempt to deal with the cause of stress and repair the damage caused by it
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