Guilty as CHARGED: p53's expanding role in disease

Cell Cycle. 2014;13(24):3798-807. doi: 10.4161/15384101.2014.987627.

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.

Keywords: CHARGE syndrome; CHD7; Mdm2; Ribosomopathy; embryonic development; neural Crest; p53; transcriptional activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • DNA Helicases / chemistry
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Embryo, Mammalian / metabolism
  • Embryonic Development
  • Genetic Diseases, X-Linked / genetics
  • Genetic Diseases, X-Linked / metabolism
  • Genetic Diseases, X-Linked / pathology
  • Hearing Loss, Conductive / genetics
  • Hearing Loss, Conductive / metabolism
  • Hearing Loss, Conductive / pathology
  • Limb Deformities, Congenital / genetics
  • Limb Deformities, Congenital / metabolism
  • Limb Deformities, Congenital / pathology
  • Maxillofacial Abnormalities / genetics
  • Maxillofacial Abnormalities / metabolism
  • Maxillofacial Abnormalities / pathology
  • Mice
  • Protein Binding
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Transcriptional Activation
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • DNA-Binding Proteins
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • DNA Helicases
  • CHD7 protein, human

Supplementary concepts

  • Abruzzo Erickson syndrome