RRC ID 5586
Author Santoriello C, Deflorian G, Pezzimenti F, Kawakami K, Lanfrancone L, d'Adda di Fagagna F, Mione M.
Title Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells.
Journal 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.
Volume 2(1-2)
Pages 56-67
Published 2009-1
DOI 10.1242/dmm.001016
PMID 19132118
PMC PMC2615164
MeSH 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*
IF 4.028
Times Cited 33
Zebrafish T2KSAG?