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Dr. Gregg L. Semenza

M.D., Ph.D.
(410) 955-3071 (p)
Interests

Genetic syndromes due to mutations in genes encoding transcription factors

Titles

C. Michael Armstrong Professor, Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, Biological Chemistry, and the McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine

Director, Vascular Program, Johns Hopkins Institue for Cell Engineering

Schools\Degrees

M.D., University of Pennsylvania Ph.D., University of Pennsylvania

Clinical Interests

Cancer Biology

Breast Cancer

Research Summary

 Dr. Semenza’s laboratory discovered hypoxia-inducible factor 1 (HIF-1), a transcription factor that controls angiogenesis, glucose metabolism, and other responses to reduced O2 availability. Overexpression of the HIF-1? subunit is associated with increased patient mortality in a wide variety of human cancers. The Semenza lab has identified several drugs, including digoxin and acriflavine, which inhibit HIF-1 activity and block tumor growth in animal models.

Journal Citations

Kim, J.W.; Tchernyshyov, I.; Semenza, G.L.; Dang, C.V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell metabolism. 2006 Mar;3(3):177-185.

Semenza, G.L. Baffled by bafilomycin: an anticancer agent that induces hypoxia-inducible factor-1alpha expression. Molecular pharmacology. 2006 Dec;70(6):1841-1843.

Semenza, G.L. VHL and p53: tumor suppressors team up to prevent cancer. Mol Cell. 2006 May 19;22(4):437-439.

Semenza, G.L. Development of novel therapeutic strategies that target HIF-1. Expert opinion on therapeutic targets. 2006 Apr;10(2):267-280.

Zhou, Y.F.; Bosch-Marce, M.; Okuyama, H.; Krishnamachary, B.; Kimura, H.; Zhang, L.; Huso, D.L.; Semenza, G.L. Spontaneous transformation of cultured mouse bone marrow-derived stromal cells. Cancer Res. 2006 Nov 15;66(22):10849-10854.

Fukuda, R.; Zhang, H.; Kim, J.W.; Shimoda, L.; Dang, C.V.; Semenza, G.L. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007 Apr 6;129(1):111-122.

Gao, P.; Zhang, H.; Dinavahi, R.; Li, F.; Xiang, Y.; Raman, V.; Bhujwalla, Z.M.; Felsher, D.W.; Cheng, L.; Pevsner, J.; Lee, L.A.; Semenza, G.L.; Dang, C.V. HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell. 2007 Sep;12(3):230-238.

Kim, J.W.; Gao, P.; Liu, Y.C.; Semenza, G.L.; Dang, C.V. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol. 2007 Nov;27(21):7381-7393.

Cai, Z.; Zhong, H.; Bosch-Marce, M.; Fox-Talbot, K.; Wang, L.; Wei, C.; Trush, M.A.; Semenza, G.L. Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1 alpha. Cardiovascular research. 2008 Feb 1;77(3):463-470.

Oda, S.; Oda, T.; Nishi, K.; Takabuchi, S.; Wakamatsu, T.; Tanaka, T.; Adachi, T.; Fukuda, K.; Semenza, G.L.; Hirota, K. Macrophage migration inhibitory factor activates hypoxia-inducible factor in a p53-dependent manner. PLoS ONE. 2008;3(5):e2215.

Semenza, G.L. Tumor metabolism: cancer cells give and take lactate. J Clin Invest. 2008 Dec;118(12):3835-3837.

Semenza, G.L. Hypoxia-inducible factor 1 and cancer pathogenesis. IUBMB Life. 2008 Sep;60(9):591-597.

Sullivan, R.; Pare, G.C.; Frederiksen, L.J.; Semenza, G.L.; Graham, C.H. Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Mol Cancer Ther. 2008 Jul;7(7):1961-1973.

Tan, M.; Gu, Q.; He, H.; Pamarthy, D.; Semenza, G.L.; Sun, Y. SAG/ROC2/RBX2 is a HIF-1 target gene that promotes HIF-1 alpha ubiquitination and degradation. Oncogene. 2008 Feb 28;27(10):1404-1411.

Zhang, H.; Qian, D.Z.; Tan, Y.S.; Lee, K.; Gao, P.; Ren, Y.R.; Rey, S.; Hammers, H.; Chang, D.; Pili, R.; Dang, C.V.; Liu, J.O.; Semenza, G.L. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19579-19586.

Ganten, D.; Semenza, G.L.; Nolte, C. Fostering trust-- Mol Med's scientific integrity policy. J Mol Med. 2009 Jan;87(1):1-2.

Guo, J.; Lu, W.; Shimoda, L.A.; Semenza, G.L.; Georas, S.N. Enhanced interferon-gamma gene expression in T Cells and reduced ovalbumin-dependent lung eosinophilia in hypoxia-inducible factor-1-alpha-deficient mice. Int Arch Allergy Immunol. 2009;149(2):98-102.

Kizaka-Kondoh, S.; Itasaka, S.; Zeng, L.; Tanaka, S.; Zhao, T.; Takahashi, Y.; Shibuya, K.; Hirota, K.; Semenza, G.L.; Hiraoka, M. Selective killing of hypoxia-inducible factor-1-active cells improves survival in a mouse model of invasive and metastatic pancreatic cancer. Clin Cancer Res. 2009 May 15;15(10):3433-3441.

Lee, K.; Qian, D.Z.; Rey, S.; Wei, H.; Liu, J.O.; Semenza, G.L. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2353-2358.

Lee, K.; Zhang, H.; Qian, D.Z.; Rey, S.; Liu, J.O.; Semenza, G.L. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17910-17915.

Rey, S.; Lee, K.; Wang, C.J.; Gupta, K.; Chen, S.; McMillan, A.; Bhise, N.; Levchenko, A.; Semenza, G.L. Synergistic effect of HIF-1alpha gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20399-20404.

Sarkar, K.; Fox-Talbot, K.; Steenbergen, C.; Bosch-Marce, M.; Semenza, G.L. Adenoviral transfer of HIF-1alpha enhances vascular responses to critical limb ischemia in diabetic mice. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18769-18774.

Schipani, E.; Maes, C.; Carmeliet, G.; Semenza, G.L. Regulation of osteogenesis-angiogenesis coupling by HIFs and VEGF. J Bone Miner Res. 2009 Aug;24(8):1347-1353.

Semenza, G.L. Regulation of vascularization by hypoxia-inducible factor 1. Ann N Y Acad Sci. 2009 Oct;1177:2-8.

Semenza, G.L. Vascular Responses to Hypoxia and Ischemia. Arterioscler Thromb Vasc Biol. 2009 Sep 3.

Semenza, G.L. HIF-1 inhibitors for cancer therapy: from gene expression to drug discovery. Curr Pharm Des. 2009;15(33):3839-3843.

Semenza, G.L. Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. Blood. 2009 Sep 3;114(10):2015-2019.

Semenza, G.L. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda). 2009 Apr;24:97-106.

Semenza, G.L. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol. 2009 Feb;19(1):12-16.

Siddiq, A.; Aminova, L.R.; Troy, C.M.; Suh, K.; Messer, Z.; Semenza, G.L.; Ratan, R.R. Selective inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways. J Neurosci. 2009 Jul 8;29(27):8828-8838.

Wikenheiser, J.; Wolfram, J.A.; Gargesha, M.; Yang, K.; Karunamuni, G.; Wilson, D.L.; Semenza, G.L.; Agani, F.; Fisher, S.A.; Ward, N.; Watanabe, M. Altered hypoxia-inducible factor-1 alpha expression levels correlate with coronary vessel anomalies. Dev Dyn. 2009 Oct;238(10):2688-2700.

Xia, M.; Huang, R.; Sun, Y.; Semenza, G.L.; Aldred, S.F.; Witt, K.L.; Inglese, J.; Tice, R.R.; Austin, C.P. Identification of chemical compounds that induce HIF-1alpha activity. Toxicol Sci. 2009 Nov;112(1):153-163.

Guan, Y.; Reddy, K.R.; Zhu, Q.; Li, Y.; Lee, K.; Weerasinghe, P.; Prchal, J.; Semenza, G.L.; Jing, N. G-rich oligonucleotides inhibit HIF-1alpha and HIF-2alpha and block tumor growth. Mol Ther. 2010 Jan;18(1):188-197.

Le, A.; Cooper, C.R.; Gouw, A.M.; Dinavahi, R.; Maitra, A.; Deck, L.M.; Royer, R.E.; Vander Jagt, D.L.; Semenza, G.L.; Dang, C.V. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2037-2042.

Semenza, G. L. 2010. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625-634.
Le, A., Cooper, C. R., Gouw, A. M., Dinavahi, R., Maitra, A., Deck, L. M., Royer, R. E., Vander Jagt, D. L., Semenza, G. L., and Dang, C. V. 2010. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl. Acad. Sci. USA 107:2037-20342.

Yoshida, T., Zhang, H., Iwase, T., Shen, J., Semenza, G. L., and Campochiaro, P. A. 2010. Digoxin inhibits retinal ischemia-induced HIF-1? expression and ocular neovascularization. FASEB J. 24:1759-1767.
Luo, W., Zhong, J., Chang, R., Hu, H., Pandey, A., and Semenza, G. L. 2010. Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1? but not HIF-2?. J. Biol. Chem. 285:3651-3663.
Semenza, G. L. 2009. HIF-1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 20:51-56.
Lee, K., Zhang, H., Qian, D. Z., Rey, S., Liu, J. O., and Semenza, G. L. 2009. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc. Natl. Acad. Sci. USA 106:17910-17915.
Semenza, G. L. 2009. HIF-1 inhibitors for cancer therapy: from gene expression to drug discovery. Curr. Pharm. Des. 15:3839-3843.

Lee, K., Qian, D. Z., Rey, S., Wei, H., Liu, J. O., and Semenza, G. L. 2009. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc. Natl. Acad. Sci. USA 106:2353-2358.

Semenza, G. L. 2009. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin. Cancer Biol. 19:12-16.

Zhang, H., Qian, D. Z., Tan, Y. S., Lee, K., Gao, P., Ren, Y. R., Rey, S., Hammers, H., Chang, D., Pili, R., Dang, C. V., Liu, J. O., and Semenza, G. L. 2008. Digoxin and other cardiac glycosides inhibit HIF-1? synthesis and block tumor growth. Proc. Natl. Acad. Sci. USA 105:19579-19586.

Sullivan, R., Pare, G. C., Frederiksen, L. J., Semenza, G. L., and Graham, C. H. 2008. Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor 1 activity. Mol. Cancer Ther. 7:1961-1973.

Semenza, G. L. 2008. Hypoxia-inducible factor 1 and cancer pathogenesis. IUBMB Life 60:591-597.

Zhang, H., Bosch-Marce, M., Shimoda, L. A., Tan, Y. S., Baek, J. H., Wesley, J. B., Gonzalez, F. J., and Semenza, G. L. 2008. Mitochondrial autophagy is a HIF-1-dependent adaptive metabolic response to hypoxia. J. Biol. Chem. 283:10892-10903.

Semenza, G. L. 2007. HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J. Bionerg. Biomembr. 39:231-234.

Zhang, H., Gao, P., Fukuda, R., Kumar, G., Krishnamachary, B., Zeller, K. I., Dang, C. V., and Semenza, G. L. 2007. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11: 407-420.

Krishnamachary, B., and Semenza, G. L. 2007. Analysis of hypoxia-inducible factor 1? expression and its effects on invasion and metastasis. Meth. Enzymol. 435: 437-354.

Fukuda, R., Zhang, H., Kim, J.-w., Shimoda, L., Dang, C. V., and Semenza, G. L. 2007. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129: 111-122.

Semenza, G. L. 2007. Life with oxygen. Science 318:62-64.

Semenza, G. L. 2007. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci. STKE 2007 Oct 9;2007(407):cm8. [Sci. STKE (Connections Map in the Database of Cell Signaling), http://stke.sciencemag.org/cgi/cm/stkecm;CMP_19178 (2007).]

Liu, Y. V., Baek, J. H., Zhang, H., Diez, R., Cole, R. N., and Semenza, G. L. 2007. RACK1 competes with HSP90 for binding to HIF-1? and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1?. Mol. Cell 25: 207-217.

Semenza, G. L. 2007. Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem. J. 405:1-9.

Liu, Y. V., and Semenza, G. L. 2007. RACK1 vs HSP90: competition for HIF-1? degradation vs stabilization. Cell Cycle 6:656-659.

Gao, P., Zhang, H., Dinavahi, R., Li, F., Xiang, Y., Raman, V., Bhujwalla, Z. M., Felsher, D. W., Cheng, L., Pevsner, J., Lee, L. A., Semenza, G. L., and Dang, C. V. 2007. HIF-1-dependent anti-tumorigenic effect of antioxidants in vivo. Cancer Cell 12: 230-238.

Semenza, G. L. 2007. Hypoxia and cancer. Cancer Metastasis Rev. 26:223-224.

Krishnamachary, B., Zagzag, D., Nagasawa, H., Rainey, K., Okuyama, H., Baek, J. H., and Semenza, G. L. 2006. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res. 66: 2725-2731.

Kim, J.-w., Tchernyshyov, I., Semenza, G. L., and Dang, C. V. 2006. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3: 177-185.

Zhou, Y. F., Bosch-Marce, M., Okuyama, H., Krishnamachary, B., Kimura, H., Zhang, L., Huso, D. L., and Semenza, G. L. 2006. Spontaneous transformation of cultured mouse bone marrow-derived stromal cells. Cancer Res. 66: 10849-10854.

Semenza, G. L. 2006. Development of novel therapeutic strategies that target HIF-1. Expert Opin. Ther. Targets 10, 267-280.

 

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