Department of Pediatrics, Medicine, Oncology, and Radiation Oncology
Molecular Mechanisms of Oxygen Homeostasis. We have cloned and characterized hypoxia-inducible factor 1 (HIF-1), a basic helix-loop-helix transcription factor. HIF-1 expression increases exponentially as cellular O2 concentration declines. HIF-1 activates transcription of genes that are essential for adaptive responses to hypoxia such as glycolysis, erythropoiesis, angiogenesis, and vascular remodeling. We are presently investigating the role of HIF-1 in the pathophysiology of cancer, cerebral and myocardial ischemia, and chronic lung disease, which are the most common causes of mortality in the U.S. population.
1. Molecular Mechanisms of Oxygen Homeostasis. We have cloned and characterized hypoxia-inducible factor 1 (HIF-1), a basic helix-loop-helix transcription factor. HIF-1 expression increases exponentially as cellular O2 concentration declines. HIF-1 activates transcription of genes that are essential for adaptive responses to hypoxia such as glycolysis, erythropoiesis, angiogenesis, and vascular remodeling. We are presently investigating the role of HIF-1 in the pathophysiology of cancer, cerebral and myocardial ischemia, chronic lung disease, and diabetes, which are the most common causes of mortality in the U.S. population.
2. Gene and Stem Cell Therapy for Ischemic Cardiovascular Disease. We are performing preclinical studies to investigate the use of adenoviral vectors encoding a constitutively active form of the HIF-1ÿ subunit to stimulate vascularization of ischemic tissue. We are also utilizing bone marrow-derived angiogenic cells and adipose-derived mesenchymal stem - cells to stimulate vascularization and tissue regeneration in preclinical models of peripheral arterial disease.
3. Role of HIF-1 in Cancer. We are investigating the effects of altered HIF-1 activity on tumor growth, metabolism, and vascularization in preclinical models. These studies are providing proof-of-principle that inhibition of HIF-1 activity represents a novel strategy of cancer therapy. We have identified several drugs that potently inhibit HIF-1 and block the growth and vascularization of human tumor xenografts in nude mice.
4. Protection of the Heart Against Ischemia-Reperfusion Injury. We have demonstrated in preclinical models that recombinant human erythropoietin induces dramatic acute protection against cell death in hearts subjected to ischemia and reperfusion via activation of the phosphatidylinositol-3-kinase signal-transduction pathway. We have shown that HIF-1 is required for ischemic preconditioning.
- Board Certification: Founding Fellow of the American College of Medical Genetics (1992)
- Licensed Physician, State of Maryland (1990)
- Diplomate of American Board of Medical Genetics (1990)
- Diplomate of the American Board of Pediatrics (1989)
- Preceptor: Predoctoral Training Program in Human Genetics, Medical Genetics Training Program, Graduate Program in Cellular and Molecular Medicine, Multidisciplinary Training Program in Lung Disease, Hematology Training Program, Basic Science Training in Nephrology, and Minority Summer Internship Program.
- Courses taught: Advanced Topics in Human Genetics course (Human Genetics), CMM Core Discussion Group (Cellular and Molecular Medicine), Journal Club (Human Genetics), The Short Course in Medical and Experimental Mammalian Genetics (The Jackson Laboratory, Bar Harbor, ME)
- Textbook: Semenza, GL: Transcription Factors and Human Disease. Oxford University Press, New York, 1998 Links: Jackson Laboratory-Annual Short Course in Medical and Experimental Mammalian Genetics Medical Genetics (Genetic Medicine) Clinical Residencey Program and Genetic Subspecialty Postdoctoral Fellowships Predoctoral Training Program in Human Genetics
- Textbook: Semenza, GL: Transcription Factors and Human Disease. Oxford University Press, New York, 1998.
- Awards: E. Mead Johnson Award for Research in Pediatrics (2000); Jean and Nicholas Leone Award, Children's Brain Tumor Foundation (1999); Established Investigator Award, American Heart Association (1994); Lucille P. Markey Scholar Award in Biomedical Science (1989); Alpha Omega Alpha Honor Medical Society (1981)
- Elected Professional Societies: National Academy of Sciences USA (2008), Association of American Physicians (2008), American Society for Clinical Investigation (1995); Society for Pediatric Research (1991)
- Editorial boards: Antioxidants and Redox Signaling (2003-present); Cancer Research (2003-Present); Cardiovascular Research (2003-present); Circulation Research (2003-present); Journal of Clinical Investigation (2000-present); Journal of Molecular Medicine (Editor-in-Chief, 2007-present); Molecular and Cellular Biology (2008-present)
- Administrative Appointment: Director, Vascular Program, The Johns Hopkins Institute for Cell Engineering (2003-present)
Wang GL, Jiang B-H, Rue EA, and Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA 92, 5510-5514, 1995. Abstract
Forsythe, JA, Jiang, B-H, Iyer, NV, Agani, F, Leung, SW, Koos, RD, and Semenza, GL: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 16, 4604-4613, 1996. Abstract
Winograd, J, Reilly, MP, Roe, R, Lutz, J, Laughner, E, Xu, X, Hu, L, Asakura, T, Vander Kolk, C, Strandberg, JD, and Semenza, GL: Perinatal lethality and multiple craniofacial malformations in MSX2 transgenic mice. Hum. Mol. Genet. 6, 369-379, 1997. Abstract
Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wegner R, Gassman M, Gearhart JD, Lawler AM, Yu AY, Semenza GL: Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Deve 12:149-162, 1998. Abstract
Yu, AY, Shimoda, LA, Iyer, NV, Huso, DL, Sun, X, McWilliams, R, Beaty, T, Sham, JSK, Wiener, CM, Sylvester, JT, and Semenza, GL: Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. J. Clin. Invest. 103, 691-696, 1999. Abstract
Zhong, H, De Marzo, AM, Laughner, E, Lim, M, Hilton, DA, Zagzag, D, Buechler, P, Isaacs, WB, Semenza, GL, and Simons, JW: Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 59, 5830-5835, 1999. Abstract
Ravi, R, Mookerjee, B, Bhujwalla, ZM, Sutter, CH, Artemov, D, Zeng, Q, Dillehay, LE, Madan, A, Semenza, GL, and Bedi, A: Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev. 14, 34-44, 2000. Abstract
Laughner, E, Taghavi, P, Chiles, K, Mahon, PC, and Semenza, GL : HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol. Cell. Biol. 21, 3995-4004, 2001. Abstract
Semenza, GL: HIF-1, O2, and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell 107, 1-3, 2001. Abstract
Mahon, P C, Hirota, K, and Semenza, GL: FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 15, 2675-2686, 2001. Abstract
Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, and Semenza GL. Expression of hypoxia-inducible factor 1a: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res. 61, 2911-2916, 2001.
Laughner E, Taghavi P, Chiles K, Mahon PC, and Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1a (HIF-1a) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol. Cell. Biol. 21, 3995-4004, 2001.
Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM, and Semenza GL. IGF-1 induces HIF-1 mediated VEGF expression that is dependent on MAP kinase and PI-3-kinase signaling in colon cancer cells. J. Biol. Chem. 277, 38205-38211, 2002.
Cai Z, Manalo DJ, Wei G, Rodriguez ER, Fox-Talbot K, Lu H, Zweier JL, and Semenza GL. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation 108: 79-85, 2003.
Semenza GL. Angiogenesis in ischemic and neoplastic disorders. Annu. Rev. Med. 54: 17-28, 2003.
Semenza GL. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3: 721-732, 2003.
Kelly BD, Hackett SF, Hirota K, Oshima Y, Cai Z, Berg-Dixon S, Rowan A, Yan Z, Campochiaro PA, and Semenza GL. Cell-type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in non-ischemic tissue by a constitutively-active form of hypoxia-inducible factor 1. Circ. Res. 93: 1074-1081, 2003.
Cai Z, and Semenza GL. Phosphatidylinositol-3-kinase signaling is required for erythropoietin-mediated acute protection against myocardial ischemia-reperfusion injury. Circulation 109: 2050-2053, 2004.
Semenza GL. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology 19: 176-182, 2004.
Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, Garcia JGN, and Semenza GL. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105: 661-671, 2005.
Baek JH, Mahon PC, Oh J, Kelly B, Krishnamachary B, Pearson M, Chan DA, Giaccia AJ, and Semenza GL. OS-9 interacts with hypoxia inducible factor 1a and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1a. Mol. Cell 17: 503-512, 2005.
Zagzag D, Krishnamachary B, Yee H, Okuyama H, Chiriboga L, Ali MA, Melamed J, and Semenza GL. Stromal cell-derived factor 1a and CXCR4 expression in hemangioblastoma and renal clear cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res. 65: 6178-6188, 2005.
Resar JR, Roguin A, Voner J, Nasir K, Hennebry TA, Miller JM, Ingersoll R, Kasch LM, and Semenza GL. Hypoxia inducible factor 1a polymorphism and coronary collaterals in patients with ischemic heart disease. Chest 128: 787-791, 2005.
Patel TH, Kimura H, Weiss CR, Semenza GL, and Hofmann LV. Constitutively active HIF-1a improves perfusion and arterial remodeling in an endovascular model of limb ischemia. Cardiovasc. Res. 68: 144-154, 2005.
Cai Z, and Semenza GL. PTEN activity is modulated during ischemia and reperfusion: involvement in the induction and decay of preconditioning. Circ. Res. 97: 1351-1359, 2005.
Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, and Semenza GL. 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, 2006.
Semenza GL, Shimoda LA, and Prabhakar NR. Regulation of gene expression by hypoxia-inducible factor 1. Novartis Found. Symp. 272: 2-8, 2006.
Semenza GL. Development of novel therapeutic strategies that target HIF-1. Expert Opin. Ther. Targets 10: 267-280, 2006.
Kim J-w, Tchernyshyov I, Semenza GL, and Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3: 177-185, 2006.
Okuyama H, Krishnamachary B, Zhou YF, Nagasawa H, Bosch-Marce M, and Semenza GL. Expression of vascular endothelial growth factor receptor 1 in bone marrow-derived mesenchymal cells is dependent on hypoxia-inducible factor 1. J. Biol. Chem. 281: 15554-15563, 2006.
Peng Y, Yuan G, Ramakrishnan D, Sharma SD, Bosch-Marce M, Kumar GK, Semenza GL, and Prabhakar NR. Heterozygous HIF-1a deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J. Physiol. 577: 705-716, 2006.
Shimoda LA, Fallon M, Pisarcik S, Wang J, Semenza GL. HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes. Am. J. Physiol. 291: 941-949, 2006.
Liu YV, Baek JH, Zhang H, Diez R, Cole RN, and Semenza GL. RACK1 competes with HSP90 for binding to HIF-1a and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1a. Mol. Cell 25: 207-217, 2007.
Fukuda R, Zhang H, Kim J-w, Shimoda L, Dang CV, and Semenza GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129: 111-122, 2007.
Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, and Semenza GL. 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, 2007.
Baek JH, Liu YV, McDonald KR, Wesley JB, Hubbi ME, Byun H, and Semenza GL. Spermidine/spermine-N1-acetyltransferase 2 is an essential component of the ubiquitin ligase complex that regulates hypoxia-inducible factor 1a. J. Biol. Chem. 282: 23572-23580, 2007.
Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V, Bhujwalla ZM, Felsher DW, Cheng L, Pevsner J, Lee LA, Semenza GL, and Dang CV. HIF-1-dependent anti-tumorigenic effect of antioxidants in vivo. Cancer Cell 12: 230-238, 2007.
Semenza GL. Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem. J. 405: 1-9, 2007.
Semenza GL. Life with oxygen. Science 318: 62-64, 2007.
Semenza GL. 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).]
Baek JH, Liu YV, McDonald KR, Wesley JB, Zhang H, and Semenza GL. Spermidine/spermine-N1-acetyltransferase-1 binds to hypoxia-inducible factor-1a (HIF-1a) and RACK1 and promotes ubiquitination and degradation of HIF-1a. J. Biol. Chem. 282: 33358-33366, 2007.
Semenza GL. Vasculogenesis, angiogenesis, and arteriogenesis: mechanisms of blood vessel formation and remodeling. J. Cell. Biochem. 102: 840-847, 2007.
Bosch-Marce M, Okuyama H, Wesley JB, Sarkar K, Kimura H, Liu YV, Zhang H, Strazza M, Rey S, Savino L, Zhou YF, McDonald KR, Na Y, Vandiver S, Rabi A, Shaked Y, Kerbel R, LaVallee T, and Semenza GL. Effects of aging and HIF-1 activity on angiogenic cell mobilization and recovery of perfusion following limb ischemia. Circ. Res. 101:1310-1318, 2007.
Liu YV, Hubbi ME, Pan F, McDonald KR, Mansharamani M, Cole RN, Liu JO, and Semenza GL. Calcineurin promotes hypoxia-inducible factor 1a expression by dephosphorylating RACK1 and blocking RACK1 dimerization. J. Biol. Chem. 282: 37064-37073, 2007.
Cai Z, Zhong H, Bosch-Marce M, Fox-Talbot K, Wang L, Wei C, Trush MA, and Semenza GL. Complete loss of ischemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1a. Cardiovasc. Res. 77: 463-470, 2008.
Semenza GL. Hypoxia-inducible factor 1 and cancer pathogenesis. IUBMB Life 60: 591-597, 2008.
Semenza GL. Mitochondrial autophagy: life and breath of the cell. Autophagy 4 :534-536, 2008.
Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, and Semenza GL. Mitochondrial autophagy is a HIF-1-dependent adaptive metabolic response to hypoxia. J. Biol. Chem. 283: 10892-10903, 2008.
Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, Rey S, Hammers H, Chang D, Pili R, Dang CV, Liu JO, and Semenza GL. Digoxin and other cardiac glycosides inhibit HIF-1a synthesis and block tumor growth. Proc. Natl. Acad. Sci. USA, in press.
Gregg L. Semenza, M.D., Ph.D.
Johns Hopkins University School of Medicine
Institute of Genetic Medicine
733 North Broadway
Broadway Research Building, Suite 671
Baltimore, MD 21205