KUB3 amplification and overexpression in human gliomas.
Gene amplification is known to occur frequently in human glioma. Recently we reported cloning of a novel gene termed glioma-amplified sequence 16 (GAS16) by microdissection-mediated cDNA capture. In this article, we demonstrate that GAS16 results from an alternative splicing process of the Ku70 binding protein 3 (KUB3) that is essential for DNA double-strand break repair. The alternative splice product was found in glioblastoma and in normal fetal brain. We determined the amplification frequency of KUB3 in glioma with different grading. We analyzed a total of 102 glioma primary tumors and found KUB3 to be amplified in 12/82 (14%) glioblastomas, 4/13 anaplastic astrocytomas (30%), and 2/4 astrocytomas, but in none of three pilocytic astrocytomas. Northern blot analysis of glioblastoma shows a strong correlation between KUB3 amplification and overexpression. Amplification of KUB3 appears to be independent of other genetic changes frequently associated with the development of gliomas, including EGFR amplification, LOH of TP53, and LOH of chromosome 10. The KUB3 amplification and overexpression may interfere with the function of KUB3 in the DNA-PK complex involved in the maintenance of genome stability and reduction of mutation frequency.
Fischer
U
U
Institut für Humangenetik, Universität des Saarlandes, Homburg/Saar, Germany.
Hemmer
D
D
Heckel
D
D
Michel
A
A
Feiden
W
W
Steudel
W I
WI
Hulsebos
T
T
Meese
E
E
D017398:Alternative Splicing / Q000502:physiology*; D034961:Antigens, Nuclear; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D001483:Base Sequence / Q000502:physiology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002879:Chromosomes, Human, Pair 10 / Q000502:physiology; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D004265:DNA Helicases; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000502:physiology*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D018773:Genes, erbB-1 / Q000502:physiology; D016158:Genes, p53 / Q000502:physiology; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007438:Introns / Q000235:genetics; D000072200:Ku Autoantigen; D009154:Mutation / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen