title: Overexpression of NBS1 contributes to transformation through the activation of phosphatidylinositol 3-kinase/Akt.
abstract: Nijmegen breakage syndrome (NBS) is a chromosomal instability syndrome associated with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. The NBS gene product, NBS1 (p95) or nibrin, is a part of the hMre11 complex, a central player associated with double strand break repair. We previously demonstrated that c-Myc directly activates NBS1 expression. Here we have shown that constitutive expression of NBS1 in Rat1a and HeLa cells induces/enhances their transformation. Repression of endogenous NBS1 levels using short interference RNA reduces the transformation activity of two tumor cell lines. Increased NBS1 expression is observed in 40-52% of non-small cell lung carcinoma, hepatoma, and esophageal cancer samples. NBS1 overexpression stimulates phosphatidylinositol (PI) 3-kinase activity, leading to increased phosphorylation levels of Akt and its downstream targets such as glycogen synthase kinase 3beta and mammalian target of rapamycin in different cell lines and tumor samples. Transformation induced by NBS1 overexpression can be inhibited by a PI3-kinase inhibitor (LY294002). Repression of endogenous Akt expression by short interference RNA decreases the transformation activity of Rat1a cells overexpressing NBS1. These results indicate that overexpression of NBS1 is an oncogenic event that contributes to transformation through the activation of PI3-kinase/Akt.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yen-Chung
authors.initials: YC
authors.lastname: Chen
authors.forename: Yi-Ning
authors.initials: YN
authors.lastname: Su
authors.forename: Po-Chien
authors.initials: PC
authors.lastname: Chou
authors.forename: Wei-Chung
authors.initials: WC
authors.lastname: Chiang
authors.forename: Ming-Cheng
authors.initials: MC
authors.lastname: Chang
authors.forename: Liang-Shun
authors.initials: LS
authors.lastname: Wang
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Teng
authors.forename: Kou-Juey
authors.initials: KJ
authors.lastname: Wu
mesh_terms: D000362:Agar / Q000737:chemistry; D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002867:Chromones / Q000494:pharmacology; D002875:Chromosomes; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D000076228:MRE11 Homologue Protein; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D000362:Agar; D018797:Cell Cycle Proteins; D002867:Chromones; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D000076228:MRE11 Homologue Protein; D009025:Morpholines; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D020123:Sirolimus; C121766:MRE11 protein, human; C512690:Mre11 protein, rat; C512689:Mre11a protein, mouse; C112156:NBN protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat