title: Decreased expression of germinal center-associated nuclear protein is involved in chromosomal instability in malignant gliomas.
abstract: Malignant glioma (MG) is highly proliferative and invasive, with the malignant characteristics associated with aneuploidy and chromosomal instability (CIN). Here, we found that the level of germinal center-associated nuclear protein (GANP), a mammalian homologue of yeast Sac3, was markedly decreased in MGs with a poor prognosis; and thus we explored the effect of its decrease on cell-cycle progression of MG cell lines. Glioblastomas showed a significantly lower level of ganp mRNA than anaplastic astrocytomas, as measured by real-time reverse transcription-PCR, in 101 cases of adult MG. MGs of ganp(Low) expression displayed more malignant characteristics, with loss of heterozygosity on chromosome 10, epidermal growth factor receptor gene amplification, and significantly poorer prognosis than the ganp(High) group. Human diploid fibroblasts depleted of ganp mRNA by the RNA interference (RNAi) method showed a decreased percentage of S-phase cells and a cellular-senescence phenotype. MG cell lines harboring abnormalities of various cell-cycle checkpoint molecules displayed slippage of mitotic checkpoints and an increased proportion of hyperploid cells after ganp RNAi-treatment. These results suggest that GANP protects cells from cellular senescence caused by DNA damage and that a significant decrease in GANP expression leads to malignancy by generating hyperploidy and CIN.
authors.affiliation: Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ohta
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Zhenhuan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Keishi
authors.initials: K
authors.lastname: Makino
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakamura
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kuratsu
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakaguchi
mesh_terms: D000123:Acetyltransferases / Q000032:analysis / Q000502:physiology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000737:chemistry / Q000235:genetics*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D043171:Chromosomal Instability; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D016158:Genes, p53; D005910:Glioma / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D034622:RNA Interference
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000123:Acetyltransferases; C406825:MCM3AP protein, human; D066246:ErbB Receptors
references.citation: Br J Cancer. 2008 Jan 29;98(2):345-55
references.pmid: 18195712
references.citation: Genes Cells. 2007 Oct;12(10):1205-13
references.pmid: 17903179
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10279-83
references.pmid: 11526238
references.citation: J Biol Chem. 2001 Dec 21;276(51):48000-8
references.pmid: 11641399
references.citation: Oncogene. 2007 Feb 15;26(7):945-57
references.pmid: 16909107
references.citation: J Immunol. 2005 Apr 15;174(8):4485-94
references.pmid: 15814669
references.citation: J Neurooncol. 2002 Jan;56(2):159-65
references.pmid: 11995817
references.citation: Cancer Res. 2006 Jul 1;66(13):6756-62
references.pmid: 16818651
references.citation: Genes Dev. 2000 Apr 1;14(7):804-16
references.pmid: 10766737
references.citation: Genes Cells. 2002 Feb;7(2):151-62
references.pmid: 11895479
references.citation: Nat Rev Mol Cell Biol. 2002 Jan;3(1):21-9
references.pmid: 11823795
references.citation: J Biol Chem. 2003 Jun 27;278(26):24225-32
references.pmid: 12702719
references.citation: Biochim Biophys Acta. 1998 Oct 14;1378(2):F115-77
references.pmid: 9823374
references.citation: Cancer Res. 1993 Jun 15;53(12):2736-9
references.pmid: 8504413
references.citation: Nature. 2007 Aug 16;448(7155):767-74
references.pmid: 17700693
references.citation: Cancer Res. 2005 Jul 1;65(13):5925-34
references.pmid: 15994971
references.citation: Nucleic Acids Res. 2007;35(12):3893-906
references.pmid: 17537816
references.citation: EMBO Rep. 2001 Feb;2(2):119-23
references.pmid: 11258703
references.citation: Curr Opin Cell Biol. 2005 Jun;17(3):242-50
references.pmid: 15901492
references.citation: Blood. 2000 Apr 1;95(7):2321-8
references.pmid: 10733502
references.citation: N Engl J Med. 2006 Sep 7;355(10):1037-46
references.pmid: 16957149
references.citation: Genes Dev. 1999 Jun 15;13(12):1501-12
references.pmid: 10385618
references.citation: Nat Genet. 2003 Aug;34(4):369-76
references.pmid: 12923544
references.citation: Oncogene. 2001 Jan 25;20(4):420-9
references.pmid: 11313973
references.citation: Trends Cell Biol. 2007 Nov;17(11):529-36
references.pmid: 17980599
references.citation: Mol Cell. 2003 Sep;12(3):711-21
references.pmid: 14527416
references.citation: Cancer. 2002 Jul 15;95(2):249-57
references.pmid: 12124823
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):1010-5
references.pmid: 14715907
references.citation: Dev Cell. 2005 Jan;8(1):19-30
references.pmid: 15621527
references.citation: Cancer Res. 1997 Mar 15;57(6):1013-9
references.pmid: 9067261
references.citation: Mol Cell. 2005 Jun 10;18(6):711-22
references.pmid: 15949445
references.citation: Cancer Res. 1998 Feb 1;58(3):396-401
references.pmid: 9458079
references.citation: Nature. 1998 Dec 17;396(6712):643-9
references.pmid: 9872311
references.citation: Nat Rev Cancer. 2002 Aug;2(8):616-26
references.pmid: 12154354
references.citation: Hum Pathol. 2000 May;31(5):608-14
references.pmid: 10836301
references.citation: Carcinogenesis. 1999 Jul;20(7):1161-8
references.pmid: 10383885
references.citation: Cancer Res. 2003 Oct 15;63(20):6962-70
references.pmid: 14583498
references.citation: Nature. 2008 Oct 23;455(7216):1061-8
references.pmid: 18772890
references.citation: Int J Oncol. 2001 Feb;18(2):343-7
references.pmid: 11172602
references.citation: J Neurosurg. 2001 Oct;95(4):651-9
references.pmid: 11596960
references.citation: J Neurosurg. 2002 May;96(5):815-22
references.pmid: 12005388
references.citation: EMBO J. 2002 Nov 1;21(21):5843-52
references.pmid: 12411502
references.citation: Cell. 2003 Jun 13;113(6):703-16
references.pmid: 12809602