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- Title
Gene deletion of inositol hexakisphosphate kinase 2 predisposes to aerodigestive tract carcinoma.
- Authors
Morrison, B. H.; Haney, R.; Lamarre, E.; Drazba, J.; Prestwich, G. D.; Lindner, D. J.
- Abstract
Inositol hexakisphosphate kinase 2 (IP6K2), a member of the inositol hexakisphosphate kinase family, functions as a growth suppressive and apoptosis-enhancing kinase during cell stress. We created mice with a targeted deletion of IP6K2; these mice display normal embryogenesis, development, growth and fertility. Chronic exposure to the carcinogen 4-nitroquinoline 1-oxide (4-NQO, a UV-mimetic compound) in drinking water resulted in fourfold increased incidence of invasive squamous cell carcinoma (SCC) formation in the oral cavity and esophagus of the knockout (KO) mice compared to the wild-type (WT) littermates. Paradoxically, KO mice displayed relative resistance to ionizing radiation and exhibit enhanced survival following 8–10 Gy total body irradiation. Primary KO fibroblasts displayed resistance to antiproliferative effects of interferon-β and increased colony forming units following ionizing radiation. Radioresistance of KO fibroblasts was associated with accelerated DNA repair measured by comet assay. Direct microinjection of 5-PP-Ins(1,2,3,4,6)P5 (the enzymatic product of IP6K2), but not InsP6 (the substrate of IP6K2) induced cell death in SCC22A squamous carcinoma cells.Oncogene (2009) 28, 2383–2392; doi:10.1038/onc.2009.113; published online 11 May 2009
- Subjects
INOSITOL; PROTEIN kinases; EMBRYOLOGY; CANCER treatment; NITROQUINOLINE oxide
- Publication
Oncogene, 2009, Vol 28, Issue 25, p2383
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2009.113