Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells.
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.
Santoriello
Cristina
C
IFOM, the FIRC Institute for Molecular Oncology Foundation, Milan, Italy.
Deflorian
Gianluca
G
Pezzimenti
Federica
F
Kawakami
Koichi
K
Lanfrancone
Luisa
L
d'Adda di Fagagna
Fabrizio
F
Mione
Marina
M
D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence; D019465:Craniofacial Abnormalities / Q000235:genetics; D004195:Disease Models, Animal; D011905:Genes, ras / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D013577:Syndrome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015027:Zebrafish; D018631:ras Proteins / Q000235:genetics* / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D018631:ras Proteins