This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Li, L.
Right arrow Articles by Kaelin, W. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, L.
Right arrow Articles by Kaelin, W. G., Jr.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, August 2007, p. 5381-5392, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.00282-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Hypoxia-Inducible Factor Linked to Differential Kidney Cancer Risk Seen with Type 2A and Type 2B VHL Mutations{triangledown} ,{dagger}

Lianjie Li,1,2 Liang Zhang,3 Xiaoping Zhang,3 Qin Yan,1,2 Yoji Andrew Minamishima,1 Aria F. Olumi,3 Mao Mao,4 Steven Bartz,4 and William G. Kaelin Jr.1,2*

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,1 Howard Hughes Medical Institute, Chevy Chase, Maryland 20815,2 Department of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115,3 Rosetta Inpharmatics LLC, Seattle, Washington 981094

Received 15 February 2007/ Returned for modification 1 April 2007/ Accepted 17 May 2007

Clear cell carcinoma of the kidney is a major cause of mortality in patients with von Hippel-Lindau (VHL) disease, which is caused by germ line mutations that inactivate the VHL tumor suppressor gene. Biallelic VHL inactivation, due to mutations or hypermethylation, is also common in sporadic clear cell renal carcinomas. The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the alpha subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for destruction under well-oxygenated conditions. All VHL mutations linked to classical VHL disease compromise this pVHL function although some missense mutations result in a low risk of kidney cancer (type 2A VHL disease) while others result in a high risk (type 2B VHL disease). We found that type 2A mutants were less defective than type 2B mutants when reintroduced into VHL–/– renal carcinoma cells with respect to HIF regulation. A stabilized version of HIF2{alpha} promoted tumor growth by VHL–/– cells engineered to produce type 2A mutants, while knock-down of HIF2{alpha} in cells producing type 2B mutants had the opposite effect. Therefore, quantitative differences with respect to HIF deregulation are sufficient to account for the differential risks of kidney cancer linked to VHL mutations.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney Street, Mayer 457, Boston, MA 02115. Phone: (617) 632-3975. Fax: (617) 632-4760. E-mail: William_kaelin{at}dfci.harvard.edu

{triangledown} Published ahead of print on 25 May 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2007, p. 5381-5392, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.00282-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Knauth, K., Cartwright, E., Freund, S., Bycroft, M., Buchberger, A. (2009). VHL Mutations Linked to Type 2C von Hippel-Lindau Disease Cause Extensive Structural Perturbations in pVHL. J. Biol. Chem. 284: 10514-10522 [Abstract] [Full Text]  
  • Xin, H., Zhang, C., Herrmann, A., Du, Y., Figlin, R., Yu, H. (2009). Sunitinib Inhibition of Stat3 Induces Renal Cell Carcinoma Tumor Cell Apoptosis and Reduces Immunosuppressive Cells. Cancer Res. 69: 2506-2513 [Abstract] [Full Text]  
  • Bommi-Reddy, A., Almeciga, I., Sawyer, J., Geisen, C., Li, W., Harlow, E., Kaelin, W. G. Jr, Grueneberg, D. A. (2008). Kinase requirements in human cells: III. Altered kinase requirements in VHL-/- cancer cells detected in a pilot synthetic lethal screen. Proc. Natl. Acad. Sci. USA 105: 16484-16489 [Abstract] [Full Text]  
  • Ricketts, C., Woodward, E. R., Killick, P., Morris, M. R., Astuti, D., Latif, F., Maher, E. R. (2008). Germline SDHB Mutations and Familial Renal Cell Carcinoma. JNCI J Natl Cancer Inst 100: 1260-1262 [Abstract] [Full Text]  
  • Khacho, M., Mekhail, K., Pilon-Larose, K., Payette, J., Lee, S. (2008). Cancer-Causing Mutations in a Novel Transcription-Dependent Nuclear Export Motif of VHL Abrogate Oxygen-Dependent Degradation of Hypoxia-Inducible Factor. Mol. Cell. Biol. 28: 302-314 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»