title: GRIM-19 mutations fail to inhibit v-Src-induced oncogenesis.
abstract: The non-receptor tyrosine kinase Src is a major player in multiple physiological responses including growth, survival and differentiation. Overexpression and/or oncogenic mutation in the Src gene have been documented in human tumors. The v-Src protein is an oncogenic mutant of Src, which promotes cell survival, migration, invasion and division. GRIM-19 is an antioncogene isolated using a genome-wide knockdown screen. Genes associated with Retinoid-IFN-induced Mortality (GRIM)-19 binds to transcription factor STAT3 and ablates its pro-oncogenic effects while v-Src activates STAT3 to promote its oncogenic effects. However, we found that GRIM-19 inhibits the pro-oncogenic effects of v-Src independently of STAT3. Here, we report the identification of functionally inactivating GRIM-19 mutations in a set of head and neck cancer patients. While wild-type GRIM-19 strongly ablated v-Src-induced cell migration, cytoskeletal remodeling and tumor metastasis, the tumor-derived mutants (L(71)P, L(91)P and A(95)T) did not. These mutants were also incapable of inhibiting the drug resistance of v-Src-transformed cells. v-Src downregulated the expression of Pag1, a lipid raft-associated inhibitor of Src, which was restored by wild-type GRIM-19. The tumor-derived mutant GRIM-19 proteins failed to upregulate Pag1. These studies show a novel mechanism that deregulates Src activity in cancer cells.
authors.affiliation: Department of Microbiology & Immunology, Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kalakonda
authors.affiliation: Department of Microbiology & Immunology, Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Nallar
authors.affiliation: Taussig Cancer Center, Cleveland, OH, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lindner
authors.affiliation: Department of Microbiology & Immunology, Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Sun
authors.affiliation: Head & Neck Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Lorenz
authors.affiliation: Head & Neck Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lamarre
authors.affiliation: Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Reddy
authors.affiliation: Department of Microbiology & Immunology, Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: D V
authors.initials: DV
authors.lastname: Kalvakolanu
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D009247:NADH, NADPH Oxidoreductases; C439057:NDUFA13 protein, human; D015688:Oncogene Protein pp60(v-src)