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한빛사논문, 상위피인용논문
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Cancer Cell, Vol 8, 143-153, August 2005
HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability.
Abstract
Jennifer S. Isaacs,1,9,10 Yun Jin Jung,6,9 David R. Mole,7 Sunmin Lee,2 Carlos Torres-Cabala,1,3 Yuen-Li Chung,8 Maria Merino,3 Jane Trepel,2 Berton Zbar,4 Jorge Toro,5 Peter J. Ratcliffe,7 W. Marston Linehan,1 and Len Neckers1,*
1 Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892
2 Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, Maryland 20892
3 Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892
4 Laboratory of Immunobiology, National Cancer Institute, Bethesda, Maryland 20892
5 Genetic Epidemiology Branch, National Cancer Institute, Bethesda, Maryland 20892
6 Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Pusan 609-735, Korea
7 Henry Wellcome Building for Molecular Physiology, University of Oxford, Headington, Oxford OX3 7BN, United Kingdom
8 Cancer Research UK Biomedical Magnetic Resonance Research Group, Department of Basic Medical Sciences, St. George’s Hospital Medical School, London SW17 0RE, United Kingdom
*Correspondence: Len Neckers, Ph: 301 496 5899; Fax: 301 402 0922
Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892.
Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.
9 These authors contributed equally to this work.
10 Present address: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Hollings Cancer Center, 86 Jonathan Lucas Street, P.O. Box 250955, Charleston, South Carolina 29425.
1 Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892
2 Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, Maryland 20892
3 Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892
4 Laboratory of Immunobiology, National Cancer Institute, Bethesda, Maryland 20892
5 Genetic Epidemiology Branch, National Cancer Institute, Bethesda, Maryland 20892
6 Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Pusan 609-735, Korea
7 Henry Wellcome Building for Molecular Physiology, University of Oxford, Headington, Oxford OX3 7BN, United Kingdom
8 Cancer Research UK Biomedical Magnetic Resonance Research Group, Department of Basic Medical Sciences, St. George’s Hospital Medical School, London SW17 0RE, United Kingdom
*Correspondence: Len Neckers, Ph: 301 496 5899; Fax: 301 402 0922
Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892.
Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.
9 These authors contributed equally to this work.
10 Present address: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Hollings Cancer Center, 86 Jonathan Lucas Street, P.O. Box 250955, Charleston, South Carolina 29425.
논문정보
- Research article
- 2005년 08월 (BRIC 등록일 )
- 국내+국외 연구진
- 의약학 > 약학
- 120회 이상 인용된 논문 (상위피인용논문 등록일 2009-09-24)
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