Developmental Acquisition of p53 Functions

Abstract

Remarkably, the p53 transcription factor, referred to as “the guardian of the genome”, is not essential for mammalian development. Moreover, efforts to identify p53dependent 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 p53dependent 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.

Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

“…1j, Supplementary Tables 7, 8). The prediction of p53 activation is also supported by differential expression of several p53 target genes (Jaiswal et al ., 2021), such as MDM2 and PPM1D (feedback); CDKN1A, BTG2, GADD45A (cell-cycle arrest); TNFRSF10B (apoptosis), DDB2 and RRM2B (DNA- repair); FDXR (metabolism) and SESN1 (translation control) (Supplementary Table 2). Other pathways of interest related to DNA damage and p53, such as cellular response to DNA damage stimulus and DNA damage response signal transduction by p53 class mediator were specific to the aneuploid group.…”

State of the Art of Pharmacological Activators of p53 in Ocular Malignancies

“…It is noteworthy that p53 exhibits widespread expression in various regions of the brain and the entire eye of adult mice. The expression is particularly high in the retina and optic nerve, while also accounting for a substantial portion, up to 70%, p53 is expressed at high levels during normal embryogenesis and development, regulating cell cycle and apoptosis [90], in the central nervous system (CNS) as well as other anatomical compartments such as olfactory bulb and eye [91][92][93][94][95][96]. Studies in an animal model showed a marked role of p53 during early embryonic ocular development, highlighting ocular abnormalities of hyaloid vasculature, vitreal opacities, retinal folding, and nerve fiber hypoplasia in mice defective for p53, according to their genetic background [97].…”

Stem Cell Origin of Cancer: Clinical Implications for Cancer Immunity and Immunotherapy

“…Consequently, in cases of severe or excessive DNA damage, p53 induces apoptosis or senescence. Furthermore, activation of p53 suppresses pluripotency genes, such as Nanog, allowing differentiation to proceed [67,68].…”