Evidence that MIG-6 is a tumor-suppressor gene.
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.
Zhang
Y-W
YW
Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503, USA. yu-wen.zhang@vai.org
Staal
B
B
Su
Y
Y
Swiatek
P
P
Zhao
P
P
Cao
B
B
Resau
J
J
Sigler
R
R
Bronson
R
R
Vande Woude
G F
GF
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001650:Bile Duct Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015152:Blotting, Northern; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D018389:Codon, Nonsense / Q000235:genetics*; D004847:Epithelial Cells / Q000473:pathology; D066246:ErbB Receptors; D005705:Gallbladder Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D018389:Codon, Nonsense; C484017:ERRFI1 protein, human; D025521:Tumor Suppressor Proteins; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases