D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function

被引：252

作者：

Sasaki, Masato ^{[1
]}

Knobbe, Christiane B. ^{[1
,2
]}

Itsumi, Momoe ^{[1
]}

Elia, Andrew J. ^{[1
]}

Harris, Isaac S. ^{[1
,3
]}

Chio, Iok In Christine ^{[1
,3
]}

Cairns, Rob A. ^{[1
]}

McCracken, Susan ^{[1
]}

Wakeham, Andrew ^{[1
]}

Haight, Jillian ^{[1
]}

Ten, Annick You ^{[1
]}

Snow, Bryan ^{[1
]}

Ueda, Takeshi ^{[1
]}

Inoue, Satoshi ^{[1
]}

Yamamoto, Kazuo ^{[1
]}

Ko, Myunggon ^{[4
]}

Rao, Anjana ^{[4
]}

Yen, Katharine E. ^{[5
]}

Su, Shinsan M. ^{[5
]}

Mak, Tak Wah ^{[1
,3
]}

机构：

[1] Univ Hlth Network, Ontario Canc Inst, Campbell Family Inst Breast Canc Res, Toronto, ON M5G 2C1, Canada

[2] Univ Dusseldorf, Dept Neuropathol, D-40225 Dusseldorf, Germany

[3] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2C1, Canada

[4] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA

[5] Agios Pharmaceut Inc, Cambridge, MA 02139 USA

来源：

GENES & DEVELOPMENT | 2012年 / 26卷 / 18期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

metabolism; brain hemorrhage; oxidative stress; angiogenesis; basement membrane; collagen biosynthesis; ISOCITRATE DEHYDROGENASE 1; HEMATOPOIETIC STEM-CELLS; ONCOMETABOLITE; 2-HYDROXYGLUTARATE; MUTATION STATUS; OLLIER DISEASE; SELF-RENEWAL; IV COLLAGEN; MOUSE MODEL; TET2; GENE;

D O I：

10.1101/gad.198200.112

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Isocitrate dehydrogenase-1 (IDH1) R132 mutations occur in glioma, but their physiological significance is unknown. Here we describe the generation and characterization of brain-specific Idh1 R132H conditional knockin (KI) mice. Idh1 mutation results in hemorrhage and perinatal lethality. Surprisingly, intracellular reactive oxygen species (ROS) are attenuated in Idh1-KI brain cells despite an apparent increase in the NADP(+)/NADPH ratio. Idh1-KI cells also show high levels of D-2-hydroxyglutarate (D2HG) that are associated with inhibited prolyl-hydroxylation of hypoxia-inducible transcription factor-1 alpha (Hif1 alpha) and up-regulated Hif1a target gene transcription. Intriguingly, D2HG also blocks prolyl-hydroxylation of collagen, causing a defect in collagen protein maturation. An endoplasmic reticulum (ER) stress response induced by the accumulation of immature collagens may account for the embryonic lethality of these mutants. Importantly, D2HG-mediated impairment of collagen maturation also led to basement membrane (BM) aberrations that could play a part in glioma progression. Our study presents strong in vivo evidence that the D2HG produced by the mutant Idh1 enzyme is responsible for the above effects.

引用

页码：2038 / 2049

页数：12

共 59 条

[1] Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2 [J].

Amary, M. Fernanda ;

Damato, Stephen ;

Halai, Dina ;

Eskandarpour, Malihe ;

Berisha, Fitim ;

Bonar, Fiona ;

McCarthy, Stan ;

Fantin, Valeria R. ;

Straley, Kimberly S. ;

Lobo, Samira ;

Aston, Will ;

Green, Claire L. ;

Gale, Rosemary E. ;

Tirabosco, Roberto ;

Futreal, Andrew ;

Campbell, Peter ;

Presneau, Nadege ;

Flanagan, Adrienne M. .

NATURE GENETICS, 2011, 43 (12) :1262-U129

[2] IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours [J].

Amary, M. Fernanda ;

Bacsi, Krisztian ;

Maggiani, Francesca ;

Damato, Stephen ;

Halai, Dina ;

Berisha, Fitim ;

Pollock, Robin ;

O'Donnell, Paul ;

Grigoriadis, Anita ;

Diss, Tim ;

Eskandarpour, Malihe ;

Presneau, Nadege ;

Hogendoorn, Pancras C. W. ;

Futreal, Andrew ;

Tirabosco, Roberto ;

Flanagan, Adrienne M. .

JOURNAL OF PATHOLOGY, 2011, 224 (03) :334-343

[3] Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation [J].

Bajenaru, ML ;

Zhu, Y ;

Hedrick, NM ;

Donahoe, J ;

Parada, LF ;

Gutmann, DH .

MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (14) :5100-5113

[4] The blood-brain barrier: an overview - Structure, regulation, and clinical implications [J].

Ballabh, P ;

Braun, A ;

Nedergaard, M .

NEUROBIOLOGY OF DISEASE, 2004, 16 (01) :1-13

[5] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[6] Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction [J].

Belteki, G ;

Haigh, J ;

Kabacs, N ;

Haigh, K ;

Sison, K ;

Costantini, F ;

Whitsett, J ;

Quaggin, SE ;

Nagy, A .

NUCLEIC ACIDS RESEARCH, 2005, 33 (05) :1-10

[7] Angiogenesis in cancer and other diseases [J].

Carmeliet, P ;

Jain, RK .

NATURE, 2000, 407 (6801) :249-257

[8] Intracerebral tumor-associated hemorrhage caused by overexpression of the vascular endothelial growth factor isoforms VEGF(121) and VEGF(165) but not VEGF(189) [J].

Cheng, SY ;

Nagane, M ;

Huang, HJS ;

Cavenee, WK .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (22) :12081-12087

[9] Comprehensive genomic characterization defines human glioblastoma genes and core pathways [J].

Chin, L. ;

Meyerson, M. ;

Aldape, K. ;

Bigner, D. ;

Mikkelsen, T. ;

VandenBerg, S. ;

Kahn, A. ;

Penny, R. ;

Ferguson, M. L. ;

Gerhard, D. S. ;

Getz, G. ;

Brennan, C. ;

Taylor, B. S. ;

Winckler, W. ;

Park, P. ;

Ladanyi, M. ;

Hoadley, K. A. ;

Verhaak, R. G. W. ;

Hayes, D. N. ;

Spellman, Paul T. ;

Absher, D. ;

Weir, B. A. ;

Ding, L. ;

Wheeler, D. ;

Lawrence, M. S. ;

Cibulskis, K. ;

Mardis, E. ;

Zhang, Jinghui ;

Wilson, R. K. ;

Donehower, L. ;

Wheeler, D. A. ;

Purdom, E. ;

Wallis, J. ;

Laird, P. W. ;

Herman, J. G. ;

Schuebel, K. E. ;

Weisenberger, D. J. ;

Baylin, S. B. ;

Schultz, N. ;

Yao, Jun ;

Wiedemeyer, R. ;

Weinstein, J. ;

Sander, C. ;

Gibbs, R. A. ;

Gray, J. ;

Kucherlapati, R. ;

Lander, E. S. ;

Myers, R. M. ;

Perou, C. M. ;

McLendon, Roger .

NATURE, 2008, 455 (7216) :1061-1068

[10] The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases [J].

Chowdhury, Rasheduzzaman ;

Yeoh, Kar Kheng ;

Tian, Ya-Min ;

Hillringhaus, Lars ;

Bagg, Eleanor A. ;

Rose, Nathan R. ;

Leung, Ivanhoe K. H. ;

Li, Xuan S. ;

Woon, Esther C. Y. ;

Yang, Ming ;

McDonough, Michael A. ;

King, Oliver N. ;

Clifton, Ian J. ;

Klose, Robert J. ;

Claridge, Timothy D. W. ;

Ratcliffe, Peter J. ;

Schofield, Christopher J. ;

Kawamura, Akane .

EMBO REPORTS, 2011, 12 (05) :463-469

← 1 2 3 4 5 6 →