IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
21
11
2018
accepted:
18
06
2019
entrez:
3
8
2019
pubmed:
3
8
2019
medline:
20
11
2019
Statut:
ppublish
Résumé
In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.
Identifiants
pubmed: 31371825
doi: 10.1038/s41556-019-0363-9
pii: 10.1038/s41556-019-0363-9
pmc: PMC6686884
mid: NIHMS1532281
doi:
Substances chimiques
RNA, Ribosomal
0
IMP Dehydrogenase
EC 1.1.1.205
IMPDH2 protein, human
EC 1.1.1.205
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1003-1014Subventions
Organisme : NINDS NIH HHS
ID : R01 NS102669
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS089815
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS100077
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA211015
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA221747
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS073831
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS107071
Pays : United States
Références
Nat Commun. 2018 Apr 19;9(1):1561
pubmed: 29674746
Leuk Res. 2008 Jan;32(1):131-41
pubmed: 17462731
Cell Rep. 2017 Dec 19;21(12):3536-3547
pubmed: 29262332
Nature. 1975 Jul 24;256(5515):331-3
pubmed: 167289
Science. 2003 Nov 21;302(5649):1399-401
pubmed: 14631041
J Antibiot (Tokyo). 1968 Jul;21(7):463-4
pubmed: 4303502
Mass Spectrom (Tokyo). 2015;4(1):A0040
pubmed: 26819911
J Biol Chem. 1993 Dec 25;268(36):27286-90
pubmed: 7903306
Annu Rev Pharmacol Toxicol. 2010;50:131-56
pubmed: 20055700
Am J Transplant. 2004 Dec;4(12):1982-90
pubmed: 15575900
FASEB J. 2014 Aug;28(8):3290-6
pubmed: 24790035
Neoplasia. 2011 Sep;13(9):784-91
pubmed: 21969812
Cancer Res. 2011 Feb 15;71(4):1418-30
pubmed: 21159662
Annu Rev Pathol. 2014;9:1-25
pubmed: 23937436
J Natl Cancer Inst. 1977 Mar;58(3):769-70
pubmed: 839569
Cell Metab. 2018 Sep 4;28(3):369-382.e5
pubmed: 30043754
Cell Metab. 2016 Jan 12;23(1):27-47
pubmed: 26771115
Electrophoresis. 2015 Sep;36(18):2148-2155
pubmed: 25820922
J Bacteriol. 1960 Dec;80:811-7
pubmed: 13786172
Mol Cell. 2016 Jan 21;61(2):187-98
pubmed: 26774281
J Biol Chem. 2012 Mar 23;287(13):10013-20
pubmed: 22318725
Cancer Cell. 2014 Aug 11;26(2):288-300
pubmed: 25117714
Surg Neurol. 1990 May;33(5):320-4
pubmed: 1691866
Cell Metab. 2012 Jun 6;15(6):827-37
pubmed: 22682223
Nat Rev Cancer. 2018 Jan;18(1):51-63
pubmed: 29192214
Cell. 2009 Jul 23;138(2):215-9
pubmed: 19632169
Chem Rev. 2009 Jul;109(7):2903-28
pubmed: 19480389
Oncotarget. 2016 May 3;7(18):24899-907
pubmed: 27056901
Chromosoma. 2013 Dec;122(6):487-97
pubmed: 24022641
Curr Opin Drug Discov Devel. 2007 Jul;10(4):403-12
pubmed: 17659481
Science. 1967 Mar 31;155(3770):1682-4
pubmed: 6020292
Cancer Res. 2008 May 1;68(9):3286-94
pubmed: 18451155
Pediatr Int. 2002 Apr;44(2):196-8
pubmed: 11896886
Biochem Pharmacol. 1995 May 11;49(9):1323-9
pubmed: 7763314
Acta Neuropathol. 2013 May;125(5):621-36
pubmed: 23512379
Nature. 1969 Aug 23;223(5208):848-50
pubmed: 5799033
Cancer Med. 2017 Nov;6(11):2635-2645
pubmed: 28980419
Immunopharmacology. 2000 May;47(2-3):163-84
pubmed: 10878288
Cancer Res. 1963 Mar;23:313-39
pubmed: 14017275
Neuro Oncol. 2017 Jan;19(1):139-141
pubmed: 28031383
J Neurosurg. 2015 Feb;122(2):324-30
pubmed: 25397368
Cancer Cell. 2011 Mar 8;19(3):305-16
pubmed: 21397855
Cancer Cell. 2014 Jan 13;25(1):77-90
pubmed: 24434211
Blood. 2003 Jun 15;101(12):4958-65
pubmed: 12609835
Clin Chem. 2001 Jan;47(1):88-94
pubmed: 11148182
Chem Rev. 2000 Oct 11;100(10):3801-26
pubmed: 11749328
Sci Signal. 2012 Sep 11;5(241):pe38
pubmed: 22969157
Cell Rep. 2017 Jun 27;19(13):2665-2680
pubmed: 28658616
Nat Neurosci. 2017 May;20(5):661-673
pubmed: 28346452
Scand J Immunol. 1991 Feb;33(2):161-73
pubmed: 1826793
J Biol Chem. 2018 May 18;293(20):7490-7498
pubmed: 29339555
Cancer Res. 2016 Mar 1;76(5):994-8
pubmed: 26880806
Adv Exp Med Biol. 1984;165 Pt B:21-6
pubmed: 6326500
Anal Chem. 2009 Aug 1;81(15):6165-74
pubmed: 19522513
Mol Cell Biochem. 1994 Nov 9;140(1):1-22
pubmed: 7877593
J Neuropathol Exp Neurol. 2014 Jul;73(7):640-57
pubmed: 24918636
Cell. 1976 Mar;7(3):447-53
pubmed: 947552
J Autism Child Schizophr. 1976 Sep;6(3):235-52
pubmed: 1086851
Am J Surg Pathol. 2009 Sep;33(9):1355-63
pubmed: 19542873
PLoS One. 2008 Jul 16;3(7):e2722
pubmed: 18628958
Mol Cell Biol. 2000 Aug;20(16):5930-8
pubmed: 10913176
Cancer Cell. 2017 Nov 13;32(5):624-638.e5
pubmed: 29056426
Genes Dev. 2002 Dec 1;16(23):2991-3003
pubmed: 12464630
Cell. 1978 Jan;13(1):121-7
pubmed: 202397
Blood. 2015 Apr 16;125(16):2519-29
pubmed: 25691158
Eur J Appl Physiol. 2010 Dec;110(6):1155-62
pubmed: 20714766
Genes Dev. 2015 Jun 15;29(12):1203-17
pubmed: 26109046
Nature. 2005 Jan 6;433(7021):77-83
pubmed: 15635413