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
Services
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 Kim, J.-w.
Right arrow Articles by Dang, C. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kim, J.-w.
Right arrow Articles by Dang, C. V.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, November 2007, p. 7381-7393, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00440-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Hypoxia-Inducible Factor 1 and Dysregulated c-Myc Cooperatively Induce Vascular Endothelial Growth Factor and Metabolic Switches Hexokinase 2 and Pyruvate Dehydrogenase Kinase 1{triangledown} ,{dagger}

Jung-whan Kim,1,{ddagger} Ping Gao,1 Yen-Chun Liu,2 Gregg L. Semenza,1,3,4,5 and Chi V. Dang1,2,3*

Division of Hematology, Department of Medicine,1 Graduate Program of Pathobiology,2 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins,3 Institute for Cell Engineering,4 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 212055

Received 14 March 2007/ Returned for modification 24 April 2007/ Accepted 24 August 2007

Hypoxia is a pervasive microenvironmental factor that affects normal development as well as tumor progression. In most normal cells, hypoxia stabilizes hypoxia-inducible transcription factors (HIFs), particularly HIF-1, which activates genes involved in anaerobic metabolism and angiogenesis. As hypoxia signals a cellular deprivation state, HIF-1 has also been reported to counter the activity of MYC, which encodes a transcription factor that drives cell growth and proliferation. Since many human cancers express dysregulated MYC, we sought to determine whether HIF-1 would in fact collaborate with dysregulated MYC rather countering its function. Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration. We also found the collaborative induction of vascular endothelial growth factor (VEGF) by HIF-1 and dysregulated c-Myc. This study reports the previously unsuspected collaboration between HIF-1 and dysregulated MYC and thereby provides additional insights into the regulation of VEGF and the Warburg effect, which describes the propensity for cancer cells to convert glucose to lactate.


* Corresponding author. Mailing address: Ross Research Building, Room 1032, 720 Rutland Avenue, Baltimore, MD 21205. Phone: (410) 955-2773. Fax: (410) 955-0185. E-mail: cvdang{at}jhmi.edu

{triangledown} Published ahead of print on 4 September 2007.

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

{ddagger} Present address: Department of Anatomy, University of California, San Francisco, HSW 1301, 513 Parnassus Ave., San Francisco, CA 94131.


Molecular and Cellular Biology, November 2007, p. 7381-7393, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00440-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.




This article has been cited by other articles:

  • Dang, C. V., Le, A., Gao, P. (2009). MYC-Induced Cancer Cell Energy Metabolism and Therapeutic Opportunities. Clin. Cancer Res. 15: 6479-6483 [Abstract] [Full Text]  
  • Tennant, D. A., Duran, R. V., Boulahbel, H., Gottlieb, E. (2009). Metabolic transformation in cancer. Carcinogenesis 30: 1269-1280 [Abstract] [Full Text]  
  • Li, C., Kim, S.-W., Rai, D., Bolla, A. R., Adhvaryu, S., Kinney, M. C., Robetorye, R. S., Aguiar, R. C. T. (2009). Copy number abnormalities, MYC activity, and the genetic fingerprint of normal B cells mechanistically define the microRNA profile of diffuse large B-cell lymphoma. Blood 113: 6681-6690 [Abstract] [Full Text]  
  • Mole, D. R., Blancher, C., Copley, R. R., Pollard, P. J., Gleadle, J. M., Ragoussis, J., Ratcliffe, P. J. (2009). Genome-wide Association of Hypoxia-inducible Factor (HIF)-1{alpha} and HIF-2{alpha} DNA Binding with Expression Profiling of Hypoxia-inducible Transcripts. J. Biol. Chem. 284: 16767-16775 [Abstract] [Full Text]  
  • Wu, H., Zhu, H., Liu, D. X., Niu, T.-K., Ren, X., Patel, R., Hait, W. N., Yang, J.-M. (2009). Silencing of Elongation Factor-2 Kinase Potentiates the Effect of 2-Deoxy-D-Glucose against Human Glioma Cells through Blunting of Autophagy. Cancer Res. 69: 2453-2460 [Abstract] [Full Text]  
  • Mahajan, S., Dammai, V., Hsu, T., Kraft, A.S. (2008). Hypoxia-inducible factor-2{alpha} regulates the expression of TRAIL receptor DR5 in renal cancer cells. Carcinogenesis 29: 1734-1741 [Abstract] [Full Text]  
  • Richards, J. G., Sardella, B. A., Schulte, P. M. (2008). Regulation of pyruvate dehydrogenase in the common killifish, Fundulus heteroclitus, during hypoxia exposure.. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295: R979-R990 [Abstract] [Full Text]  
  • Yuan, S., Fu, Y., Wang, X., Shi, H., Huang, Y., Song, X., Li, L., Song, N., Luo, Y. (2008). Voltage-dependent anion channel 1 is involved in endostatin-induced endothelial cell apoptosis. FASEB J. 22: 2809-2820 [Abstract] [Full Text]  
  • Gillies, R. J., Robey, I., Gatenby, R. A. (2008). Causes and Consequences of Increased Glucose Metabolism of Cancers. JNM 49: 24S-42S [Abstract] [Full Text]  
  • Nikiforov, M. A., Riblett, M., Tang, W.-H., Gratchouck, V., Zhuang, D., Fernandez, Y., Verhaegen, M., Varambally, S., Chinnaiyan, A. M., Jakubowiak, A. J., Soengas, M. S. (2007). Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. Proc. Natl. Acad. Sci. USA 104: 19488-19493 [Abstract] [Full Text]