Abstract
The tumor suppressor p53 is critical for preventing neoplastic transformation and tumor progression. Inappropriate activation of p53, however, has been observed in a number of human inherited disorders that most often affect development of the brain, craniofacial region, limb skeleton, and hematopoietic system. Genes related to these developmental disorders are essentially involved in transcriptional regulation/chromatin remodeling, rRNA metabolism, DNA damage-repair pathways, telomere maintenance, and centrosome biogenesis. Perturbation of these activities or cellular processes may result in p53 accumulation in cell cultures, animal models, and perhaps humans as well. Mouse models of several p53 activation-associated disorders essentially recapitulate human traits, and inactivation of p53 in these models can alleviate disorder-related phenotypes. In the present review, we focus on how dysfunction of the aforementioned biological processes causes developmental defects via excessive p53 activation. Notably, several disease-related genes exert a pleiotropic effect on those cellular processes, which may modulate the magnitude of p53 activation and establish or disrupt regulatory loops. Finally, we discuss potential therapeutic strategies for genetic disorders associated with p53 misactivation.
Highlights
Over the past two decades, studies using tissue/cell-specific knockout mice have revealed that disruption of certain cellular processes can upregulate p53 and recapitulate developmental defects observed in the corresponding human disorders
P53 suppression often partially rescues the mutant phenotypes of animal models of the aforementioned disorders, indicating that individual disorder-related factors may have specialized roles in cellular functions and development
It must be noted that murine p53 isoforms are similar but not identical to their human counterparts
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. P53 transactivates approximately one hundred target genes that exert diverse biological functions—primarily cell cycle regulation, DNA repair, and apoptosis [2,3]. Trp knockout mice exhibit developmental abnormalities, which, differ between strains of mice with different genetic backgrounds, indicating that p53 contributes to cell differentiation and development [5]. P53 regulates cell senescence and aging through multiple signaling pathways [7]. Excessive p53 activation during embryonic development has been observed in a variety of congenital disorders [10]. We discuss several sets of genetic mutations that contribute to excessive p53 activation, leading to phenotypic abnormalities in congenital disorders
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