Abstract

Germ line mutation of the von Hippel-Lindau (VT-IL) tumor suppressor gene causes a hereditary cancer syndrome characterized by blood vessel tumors (hemangioblastomas) of the central nervous system and retina, renal cell carcinomas, and pheochromocytomas. Somatic VHL inactivation is common in sporadic renal cell carcinomas and hemangioblastomas. The VFIL gene product, pVHL, forms a multimeric complex that contains elongin B, elongin C, Cu12, and Rbx1. This complex is an E3 ubiquitin ligase in which pVHL targets specific proteins for degradation by the proteasome. The best understood targets are HIF1a and HIF2a, two related transcription factors that regulate hypoxia-inducible genes such as VEGF. In normal cells HIF1a and HIF2a are rapidly degraded in the presence of oxygen and only become stable when cells are made hypoxic. In cells lacking pVHL these proteins can not be degraded and accumulate to high levels leading to activation of HIF target genes. How pVFIL is prevented from degrading HIF under hypoxic conditions is not known and is the subject of specific aim 1.
Specific aim 2 asks to what degree the set of pVHL-regulated genes and hypoxia-regulated genes overlap and specific aim 3 asks whether inhibition of HIF function is necessary and/or sufficient for tumor suppression by pVHL. Identification of additional proteins that bind to, and are regulated by, pVHL is the goal of specific aim 4.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068490-08
Application #
6633085
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mietz, Judy
Project Start
1996-08-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
8
Fiscal Year
2003
Total Cost
$283,286
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Chakraborty, Abhishek A; Nakamura, Eijiro; Qi, Jun et al. (2017) HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1 histone methyltransferase. Sci Transl Med 9:
Briggs, Kimberly J; Koivunen, Peppi; Cao, Shugeng et al. (2016) Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine. Cell 166:126-39
Olenchock, Benjamin A; Moslehi, Javid; Baik, Alan H et al. (2016) EGLN1 Inhibition and Rerouting of ?-Ketoglutarate Suffice for Remote Ischemic Protection. Cell 164:884-95
Zhang, Jing; Wang, Chengyang; Chen, Xi et al. (2015) EglN2 associates with the NRF1-PGC1? complex and controls mitochondrial function in breast cancer. EMBO J 34:2953-70
Akbay, Esra A; Moslehi, Javid; Christensen, Camilla L et al. (2014) D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. Genes Dev 28:479-90
Lu, Gang; Zhang, Qing; Huang, Ying et al. (2014) Phosphorylation of ETS1 by Src family kinases prevents its recognition by the COP1 tumor suppressor. Cancer Cell 26:222-34
Lu, Gang; Middleton, Richard E; Sun, Huahang et al. (2014) The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:305-9
Couvé, Sophie; Ladroue, Charline; Laine, Elodie et al. (2014) Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis. Cancer Res 74:6554-64
Choueiri, T K; Pal, S K; McDermott, D F et al. (2014) A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol 25:1603-8
Zheng, Xingnan; Zhai, Bo; Koivunen, Peppi et al. (2014) Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase. Genes Dev 28:1429-44

Showing the most recent 10 out of 37 publications