Gene deletion of inositol hexakisphosphate kinase 2 predisposes to aerodigestive tract carcinoma
Open Access
- 11 May 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 28 (25), 2383-2392
- https://doi.org/10.1038/onc.2009.113
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.This publication has 37 references indexed in Scilit:
- A Scalable Synthesis of the IP7 Isomer, 5-PP-Ins(1,2,3,4,6)P5Organic Letters, 2009
- Evidence for an inositol hexakisphosphate-dependent role for Ku in mammalian nonhomologous end joining that is independent of its role in the DNA-dependent protein kinaseNucleic Acids Research, 2008
- Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion, growth, and spermiogenesisProceedings of the National Academy of Sciences of the United States of America, 2008
- Requirement of Inositol Pyrophosphates for Full Exocytotic Capacity in Pancreatic β CellsScience, 2007
- Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancerProceedings of the National Academy of Sciences, 2007
- Visualization of inositol phosphate-dependent mobility of Ku: depletion of the DNA-PK cofactor InsP6 inhibits Ku mobilityNucleic Acids Research, 2004
- Expression mapping at 12p12‐13 in advanced prostate carcinomaInternational Journal of Cancer, 2004
- MAPK phosphatase DUSP16/MKP-7, a candidate tumor suppressor for chromosome region 12p12–13, reduces BCR-ABL-induced transformationOncogene, 2003
- Differential deletions in 3p are associated with the development of head and neck squamous cell carcinoma in Indian patientsCancer Genetics and Cytogenetics, 2003
- Deletion of a DNA sequence at the chromosomal region 3p21 in all major types of lung cancerNature, 1987