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Mutational activation of the MAP3K8 protooncogene in lung cancer.

Clark-AM; Reynolds-SH; Anderson-M; Wiest-JS

Genes Chromosomes Cancer 2004 Oct; 41(2):99-108

http://dx.doi.org/10.1002/gcc.20069

20025474

The MAP3K8 protooncogene (Cot/Tpl-2) activates the MAP kinase, SAP kinase, and NF-kappaB signaling pathways. MAP3K8 mutations occur in the rat homologue, but activating mutations have yet to be identified in primary human tumors. We have identified MAP3K8 as a transforming gene from a human lung adenocarcinoma and characterized a 3' end mutation in the cDNA. In addition, we confirmed that the mutation occurs in the original lung tumor, and we screened a series of lung cancer cell lines to determine whether the MAP3K8 mutation is a common occurrence in lung tumorigenesis. The oncogene was isolated and identified with the NIH3T3 nude mouse tumorigenicity assay and cDNA library screening. The gene was analyzed by polymerase chain reaction (PCR), single-strand conformational polymorphism (SSCP), and 3'RACE for mutations. The mutation was localized to MAP3K8 exon 8 and confirmed in the primary tumor DNA. Both wild-type and mutant MAP3K8 cDNAs transformed NIH3T3 cells, but the transforming activity of the mutant was much greater than that of the wild type. PCR-SSCP screening of cell line cDNAs identified one silent polymorphism in cell line SK-LU-1. Although we were unable to find additional activating mutations, these data support a role for MAP3K8 activity in cellular transformation, but suggest that mutational activation of the gene is a rare event in lung cancer.

Lung-cancer; Cancer; Pulmonary-system-disorders; Respiratory-system-disorders; Laboratory-animals; Animals; Animal-studies; Humans; Tumors; Carcinomas; Tumorigenesis

Jonathon S. Weist, National Cancer Institute, 31 Center Drive, Building 31A/Rm 3A11, Bethesda, MD 20892

GCCAES

20041001

Journal Article

wiestj@mail.nih.gov

2005

2

1045-2257

HELD

Research Tools and Approaches: Cancer Research Methods

Genes, Chromosomes and Cancer

WV; OH; MD