Abstract
Mitogen-inducible gene 6 (MIG-6) is located in human chromosome 1p36, a locus frequently associated with human lung cancer. MIG-6 is a negative regulator of epidermal growth factor (EGF) signaling, and we show that Mig-6 - like EGF - is induced by hepatocyte growth factor/scatter factor (HGF/SF) in human lung cancer cell lines. Frequently, the receptors for both factors, EGFR and Met, are expressed in same lung cancer cell line, and MIG-6 is induced by both factors in a mitogen-activated protein kinase-dependent fashion. However, not all tumor lines express MIG-6 in response to either EGF or HGF/SF. In these cases, we find missense and nonsense mutations in the MIG-6 coding region, as well as evidence for MIG-6 transcriptional silencing. Moreover, germline disruption of Mig-6 in mice leads to the development of animals with epithelial hyperplasia, adenoma, and adenocarcinoma in organs like the lung, gallbladder, and bile duct. These data suggests that MIG-6 is a tumor-suppressor gene and is therefore a candidate gene for the frequent 1p36 genetic alterations found in lung cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / physiology*
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Adenocarcinoma / etiology
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Adenoma / etiology
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Adenoma / metabolism
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Adenoma / pathology
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Animals
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Bile Duct Neoplasms / etiology
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Bile Duct Neoplasms / metabolism
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Bile Duct Neoplasms / pathology
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Blotting, Northern
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Blotting, Western
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Codon, Nonsense / genetics*
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Epithelial Cells / pathology
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ErbB Receptors
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Gallbladder Diseases / etiology
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Gallbladder Diseases / metabolism
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Gallbladder Diseases / pathology
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Gene Expression Regulation, Neoplastic
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Genes, Tumor Suppressor / physiology*
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Hepatocyte Growth Factor / pharmacology
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Humans
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Hyperplasia / etiology
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Hyperplasia / metabolism
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Hyperplasia / pathology
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Immunoenzyme Techniques
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology*
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinases / metabolism
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Mutation, Missense / genetics*
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Signal Transduction
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Tumor Cells, Cultured
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Tumor Suppressor Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Codon, Nonsense
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ERRFI1 protein, human
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Tumor Suppressor Proteins
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Hepatocyte Growth Factor
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ErbB Receptors
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Mitogen-Activated Protein Kinases