The role of senescence and prosurvival signaling in controlling the oncogenic activity of FGFR2 mutants associated with cancer and birth defects

Sara Ota, Zi Qiang Zhou, Jason Link, Peter J. Hurlin

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Mutations in fibroblast growth factor receptors (FGFRs) cause human birth defect syndromes and are associated with a variety of cancers. Although forced expression of mutant activated FGFRs has been shown to oncogenically transform some immortal cell types, their activity in primary cells remains unclear. Here, we show that birth defect and cancer-associated FGFR2 mutants promote DNA-damage signaling and p53-dependent senescence in primary mouse and human cells. Senescence promoted by FGFR mutants was associated with downregulation of c-Myc and forced expression of c-Myc facilitated senescence escape. Whereas c-Myc expression facilitated senescence bypass, mutant FGFR2 signaling suppressed c-Myc-dependent apoptosis and led to oncogenic transformation. Cells transformed by coexpression of a constitutively activated FGFR2 mutant plus c-Myc appeared to be become highly addicted to FGFR-dependent prosurvival activities, as small molecule inhibition of FGFR signaling resulted in robust p53-dependent apoptosis. Our data suggest that senescence-promoting activities of mutant FGFRs may normally limit their oncogenic potential and may be relevant to their ability to disrupt morphogenesis and cause birth defects. Our results also raise the possibility that cancers originating through a combination of constitutive FGFR activation and deregulated Myc expression may be particularly sensitive to small molecule inhibitors of FGF receptors.

Original languageEnglish (US)
Pages (from-to)2609-2621
Number of pages13
JournalHuman Molecular Genetics
Volume18
Issue number14
DOIs
StatePublished - 2009

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Fibroblast Growth Factor Receptors
Neoplasms
Apoptosis
Morphogenesis
DNA Damage
Down-Regulation
Mutation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

The role of senescence and prosurvival signaling in controlling the oncogenic activity of FGFR2 mutants associated with cancer and birth defects. / Ota, Sara; Zhou, Zi Qiang; Link, Jason; Hurlin, Peter J.

In: Human Molecular Genetics, Vol. 18, No. 14, 2009, p. 2609-2621.

Research output: Contribution to journalArticle

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