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GRIM-19 mutations fail to inhibit v-Src-induced oncogenesis

S Kalakonda1, S C Nallar1, D J Lindner2

  • 1Department of Microbiology & Immunology, Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.

Oncogene
|July 16, 2013
PubMed

Insights

Mutations in the GRIM-19 gene in head and neck cancers inactivate its tumor-suppressing function against the oncogene v-Src. Wild-type GRIM-19 inhibits v-Src

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The non-receptor tyrosine kinase Src plays a key role in cell growth, survival, and differentiation, with its dysregulation implicated in human cancers.
  • The oncogenic mutant v-Src promotes cell survival, migration, invasion, and division, contributing to tumor progression.
  • GRIM-19 (Genes associated with Retinoid-IFN-induced Mortality 19) is an antioncogene that inhibits STAT3's pro-oncogenic effects, but its role concerning v-Src was unclear.

Purpose of the Study:

  • To investigate the mechanism by which GRIM-19 inhibits the pro-oncogenic effects of v-Src.
  • To identify and characterize GRIM-19 mutations in head and neck cancer patients and assess their functional impact.
  • To elucidate the role of GRIM-19 in regulating Src activity and its downstream targets like Pag1.

Main Methods:

  • Identification of GRIM-19 mutations in head and neck cancer patient samples.
  • Functional assays assessing the ability of wild-type and mutant GRIM-19 to inhibit v-Src-induced cell migration, cytoskeletal remodeling, and metastasis.
  • Evaluation of GRIM-19's effect on drug resistance in v-Src-transformed cells.
  • Analysis of Pag1 expression levels in response to wild-type and mutant GRIM-19 and v-Src.

Main Results:

  • Functionally inactivating mutations in GRIM-19 were identified in head and neck cancer patients.
  • Wild-type GRIM-19 inhibited v-Src-induced cell migration, cytoskeletal remodeling, and metastasis, whereas tumor-derived GRIM-19 mutants (L71P, L91P, A95T) failed to do so.
  • Mutant GRIM-19 proteins were unable to inhibit drug resistance in v-Src-transformed cells.
  • v-Src downregulated Pag1 expression, an inhibitor of Src; wild-type GRIM-19 restored Pag1 levels, but the mutants did not.

Conclusions:

  • GRIM-19 inhibits the pro-oncogenic effects of v-Src independently of STAT3, through a novel mechanism involving Pag1 regulation.
  • Mutations in GRIM-19 found in head and neck cancers lead to loss of its tumor-suppressive functions.
  • These findings reveal a new pathway by which Src activity is deregulated in cancer cells, highlighting GRIM-19 as a potential therapeutic target.

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