PUBLICATION

Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells

Authors
Santoriello, C., Deflorian, G., Pezzimenti, F., Kawakami, K., Lanfrancone, L., d'Adda di Fagagna, F., and Mione, M.
ID
ZDB-PUB-090112-19
Date
2009
Source
Disease models & mechanisms   2(1-2): 56-67 (Journal)
Registered Authors
Deflorian, Gianluca, Kawakami, Koichi, Mione, Marina, Pezzimenti, Federica, Santoriello, Cristina
Keywords
none
MeSH Terms
  • Abnormalities, Multiple/genetics
  • Animals
  • Cell Proliferation
  • Cellular Senescence*
  • Craniofacial Abnormalities/genetics
  • Disease Models, Animal
  • Genes, ras/genetics*
  • Heart Defects, Congenital/genetics
  • Humans
  • Intellectual Disability/genetics
  • Mice
  • Mutation
  • NIH 3T3 Cells
  • Syndrome
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish
  • ras Proteins/genetics*
  • ras Proteins/physiology*
PubMed
19132118 Full text @ Dis. Model. Mech.
Abstract
Constitutively active, 'oncogenic' H-RAS can drive proliferation and transformation in human cancer, or be a potent inducer of cellular senescence. Moreover, aberrant activation of the Ras pathway owing to germline mutations can cause severe developmental disorders. In this study we have generated transgenic zebrafish that constitutively express low levels, or can be induced to express high levels, of oncogenic H-RAS. We observed that fish carrying the integrated transgene in their germline display several hallmarks of Costello syndrome, a rare genetic disease caused by activating mutations in the gene H-RAS, and can be used as a model for the disease. In Costello-like fish, low levels of oncogenic H-RAS expression are associated with both reduced proliferation and an increase in senescence markers in adult progenitor cell compartments in the brain and heart, together with activated DNA damage responses. Overexpression of H-RAS through a heat-shock-inducible promoter in larvae led to hyperproliferation, activation of the DNA damage response and tp53-dependent cell cycle arrest. Thus, oncogene-induced senescence of adult proliferating cells contributes to the development of Costello syndrome and provides an alternative pathway to transformation in the presence of widespread constitutively active H-RAS expression.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes