Article ; Online: GRIM-19 mutations fail to inhibit v-Src-induced oncogenesis.
2013 Volume 33, Issue 24, Page(s) 3195–3204
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 ...
| 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. |
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| MeSH term(s) | Animals ; Apoptosis ; Apoptosis Regulatory Proteins/genetics ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Blotting, Western ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/pathology ; Cell Movement ; Cell Proliferation ; Cell Transformation, Neoplastic/pathology ; Fluorescent Antibody Technique ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Immunoenzyme Techniques ; Mice ; Mice, Nude ; Mouth Neoplasms/genetics ; Mouth Neoplasms/pathology ; Mutation/genetics ; NADH, NADPH Oxidoreductases/genetics ; Oligonucleotide Array Sequence Analysis ; Oncogene Protein pp60(v-src)/genetics ; Oncogene Protein pp60(v-src)/metabolism ; Phosphorylation ; RNA, Messenger/genetics ; Rats ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays |
| Chemical Substances | Apoptosis Regulatory Proteins ; Biomarkers, Tumor ; RNA, Messenger ; STAT3 Transcription Factor ; NADH, NADPH Oxidoreductases (EC 1.6.-) ; NDUFA13 protein, human (EC 1.6.5.-) ; Oncogene Protein pp60(v-src) (EC 2.7.10.2) |
| Language | English |
| Publishing date | 2013-07-15 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 639046-8 |
| ISSN | 1476-5594 ; 0950-9232 |
| ISSN (online) | 1476-5594 |
| ISSN | 0950-9232 |
| DOI | 10.1038/onc.2013.271 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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