title: Guilty as CHARGED: p53's expanding role in disease.
abstract: Unrestrained p53 activity during development, as occurs upon loss of the p53 negative regulators Mdm2 or Mdmx, causes early embryonic lethality. Surprisingly, co-expression of wild-type p53 and a transcriptionally-dead variant of p53, with mutations in both transactivation domains (p53(L25Q,W26S,F53Q,F54S)), also causes lethality, but later in gestation and in association with a host of very specific phenotypes reminiscent of a syndrome known as CHARGE. Molecular analyses revealed that wild-type p53 is inappropriately activated in p53(5,26,53,54/)(+) embryos, triggering cell-cycle arrest or apoptosis during development to cause CHARGE phenotypes. In addition, CHARGE syndrome is typically caused by mutations in the CHD7 chromatin remodeler, and we have shown that activated p53 contributes to phenotypes caused by CHD7-deficiency. Together, these studies provide new insight into CHARGE syndrome and expand our understanding of the role of p53 in diseases other than cancer.
authors.affiliation: a Division of Radiation and Cancer Biology; Department of Radiation Oncology ; Stanford School of Medicine ; Stanford , CA USA.
authors.forename: Jeanine L
authors.initials: JL
authors.lastname: Van Nostrand
authors.forename: Laura D
authors.initials: LD
authors.lastname: Attardi
mesh_terms: D000818:Animals; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006314:Hearing Loss, Conductive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017880:Limb Deformities, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019767:Maxillofacial Abnormalities / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D004265:DNA Helicases; C491434:CHD7 protein, human
keywords: CHARGE syndrome; CHD7; Mdm2; Ribosomopathy; embryonic development; neural Crest; p53; transcriptional activation