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

AI Article Synopsis

  • Constitutively active H-RAS can cause both cancer and cellular aging, with its aberrant activation linked to developmental disorders.
  • Researchers created transgenic zebrafish that express different levels of oncogenic H-RAS to study its effects, revealing signs of Costello syndrome, which is normally caused by mutations in the same gene.
  • The study found that low H-RAS levels lead to decreased cell division and increased aging markers in certain tissues, while high levels trigger excessive cell growth and stress responses, suggesting a complex role of H-RAS in disease development.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2615164PMC
http://dx.doi.org/10.1242/dmm.001016DOI Listing

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