Reciprocal Positive Regulation of Hypoxia-inducible Factor 1{{alpha}} and Insulin-like Growth Factor 2

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Reciprocal Positive Regulation of Hypoxia-inducible Factor 1 ${alpha}$ and Insulin-like Growth Factor 2¹

David Feldser, Faton Agani, Narayan V. Iyer, Brian Pak, Gloria Ferreira and Gregg L. Semenza²

Institute of Genetic Medicine, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914

Hypoxia-inducible factor 1 (HIF-1) activates transcription ofgenes encoding glucose transporters, glycolytic enzymes, vascularendothelial growth factor, and other proteins involved in O₂homeostasis and tumor progression. The expression and transcriptionalactivity of the HIF-1 ${alpha}$ subunit is regulated by the cellular O₂concentration. We demonstrate that insulin, insulin-like growthfactor (IGF)-1, and IGF-2 induce expression of HIF-1 ${alpha}$ , whichis required for expression of genes encoding IGF-2, IGF-bindingprotein (IGFBP)-2 and IGFBP-3. These data provide a novel mechanismby which HIF-1 ${alpha}$ overexpression may occur in tumor cells and contributeto an autocrine growth factor loop.

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D. Mottet, V. Dumont, Y. Deccache, C. Demazy, N. Ninane, M. Raes, and C. Michiels
Regulation of Hypoxia-inducible Factor-1{alpha} Protein Level during Hypoxic Conditions by the Phosphatidylinositol 3-Kinase/Akt/Glycogen Synthase Kinase 3{beta} Pathway in HepG2 Cells
J. Biol. Chem., August 15, 2003; 278(33): 31277 - 31285.
[Abstract] [Full Text] [PDF]

S. T. Palayoor, P. J. Tofilon, and C. N. Coleman
Ibuprofen-mediated Reduction of Hypoxia-inducible Factors HIF-1{alpha} and HIF-2{alpha} in Prostate Cancer Cells
Clin. Cancer Res., August 1, 2003; 9(8): 3150 - 3157.
[Abstract] [Full Text] [PDF]

D. O. Bates and R. O. P. Jones
The Role of Vascular Endothelial Growth Factor in Wound Healing
International Journal of Lower Extremity Wounds, June 1, 2003; 2(2): 107 - 120.
[Abstract] [PDF]

T. N. Seagroves, D. Hadsell, J. McManaman, C. Palmer, D. Liao, W. McNulty, B. Welm, K.-U. Wagner, M. Neville, and R. S. Johnson
HIF1{alpha} is a critical regulator of secretory differentiation and activation, but not vascular expansion, in the mouse mammary gland
Development, April 15, 2003; 130(8): 1713 - 1724.
[Abstract] [Full Text] [PDF]

F. HEDBORG, E. ULLERAS, L. GRIMELIUS, E. WASSBERG, P. H MAXWELL, B. HERO, F. BERTHOLD, F. SCHILLING, D. HARMS, B. SANDSTEDT, et al.
Evidence for hypoxia-induced neuronal-to-chromaffin metaplasia in neuroblastoma
FASEB J, April 1, 2003; 17(6): 598 - 609.
[Abstract] [Full Text] [PDF]

J. P.T. Higgins, R. Shinghal, H. Gill, J. H. Reese, M. Terris, R. J. Cohen, M. Fero, J. R. Pollack, M. van de Rijn, and J. D. Brooks
Gene Expression Patterns in Renal Cell Carcinoma Assessed by Complementary DNA Microarray
Am. J. Pathol., March 1, 2003; 162(3): 925 - 932.
[Abstract] [Full Text] [PDF]

M. C. A. Duyndam, S. T. M. Hulscher, E. van der Wall, H. M. Pinedo, and E. Boven
Evidence for a Role of p38 Kinase in Hypoxia-inducible Factor 1-independent Induction of Vascular Endothelial Growth Factor Expression by Sodium Arsenite
J. Biol. Chem., February 21, 2003; 278(9): 6885 - 6895.
[Abstract] [Full Text] [PDF]

T. Kietzmann, A. Samoylenko, U. Roth, and K. Jungermann
Hypoxia-inducible factor-1 and hypoxia response elements mediate the induction of plasminogen activator inhibitor-1 gene expression by insulin in primary rat hepatocytes
Blood, February 1, 2003; 101(3): 907 - 914.
[Abstract] [Full Text] [PDF]

R. Karni, Y. Dor, E. Keshet, O. Meyuhas, and A. Levitzki
Activated pp60c-Src Leads to Elevated Hypoxia-inducible Factor (HIF)-1alpha Expression under Normoxia
J. Biol. Chem., November 1, 2002; 277(45): 42919 - 42925.
[Abstract] [Full Text] [PDF]

J. C. Chavez and J. C. LaManna
Activation of Hypoxia-Inducible Factor-1 in the Rat Cerebral Cortex after Transient Global Ischemia: Potential Role of Insulin-Like Growth Factor-1
J. Neurosci., October 15, 2002; 22(20): 8922 - 8931.
[Abstract] [Full Text] [PDF]

R. Fukuda, K. Hirota, F. Fan, Y. D. Jung, L. M. Ellis, and G. L. Semenza
Insulin-like Growth Factor 1 Induces Hypoxia-inducible Factor 1-mediated Vascular Endothelial Growth Factor Expression, Which is Dependent on MAP Kinase and Phosphatidylinositol 3-Kinase Signaling in Colon Cancer Cells
J. Biol. Chem., October 4, 2002; 277(41): 38205 - 38211.
[Abstract] [Full Text] [PDF]

R. H. WENGER
Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression
FASEB J, August 1, 2002; 16(10): 1151 - 1162.
[Abstract] [Full Text] [PDF]

F. Spinella, L. Rosano, V. Di Castro, P. G. Natali, and A. Bagnato
Endothelin-1 Induces Vascular Endothelial Growth Factor by Increasing Hypoxia-inducible Factor-1alpha in Ovarian Carcinoma Cells
J. Biol. Chem., July 26, 2002; 277(31): 27850 - 27855.
[Abstract] [Full Text] [PDF]

V. Seshadri, P. L. Fox, and C. K. Mukhopadhyay
Dual Role of Insulin in Transcriptional Regulation of the Acute Phase Reactant Ceruloplasmin
J. Biol. Chem., July 26, 2002; 277(31): 27903 - 27911.
[Abstract] [Full Text] [PDF]

H. Lu, R. A. Forbes, and A. Verma
Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis
J. Biol. Chem., June 21, 2002; 277(26): 23111 - 23115.
[Abstract] [Full Text] [PDF]

D. Dantz, J. Bewersdorf, B. Fruehwald-Schultes, W. Kern, W. Jelkmann, J. Born, H. L. Fehm, and A. Peters
Vascular Endothelial Growth Factor: A Novel Endocrine Defensive Response to Hypoglycemia
J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 835 - 840.
[Abstract] [Full Text] [PDF]

N. Akeno, J. Robins, M. Zhang, M. F. Czyzyk-Krzeska, and T. L. Clemens
Induction of Vascular Endothelial Growth Factor by IGF-I in Osteoblast-Like Cells Is Mediated by the PI3K Signaling Pathway through the Hypoxia-Inducible Factor-2{alpha}
Endocrinology, February 1, 2002; 143(2): 420 - 425.
[Abstract] [Full Text] [PDF]

J. Zhang and L.A. Salamonsen
Expression of hypoxia-inducible factors in human endometrium and suppression of matrix metalloproteinases under hypoxic conditions do not support a major role for hypoxia in regulating tissue breakdown at menstruation
Hum. Reprod., February 1, 2002; 17(2): 265 - 274.
[Abstract] [Full Text] [PDF]

A. Hoeflich, R. Reisinger, H. Lahm, W. Kiess, W. F. Blum, H. J. Kolb, M. M. Weber, and E. Wolf
Insulin-like Growth Factor-binding Protein 2 in Tumorigenesis: Protector or Promoter?
Cancer Res., December 1, 2001; 61(24): 8601 - 8610.
[Full Text] [PDF]

D. M. STROKA, T. BURKHARDT, I. DESBAILLETS, R. H. WENGER, D. A. H. NEIL, C. BAUER, M. GASSMANN, and D. CANDINAS
HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia
FASEB J, November 1, 2001; 15(13): 2445 - 2453.
[Abstract] [Full Text] [PDF]

C. Blancher, J. W. Moore, N. Robertson, and A. L. Harris
Effects of ras and von Hippel-Lindau (VHL) Gene Mutations on Hypoxia-inducible Factor (HIF)-1{alpha}, HIF-2{alpha}, and Vascular Endothelial Growth Factor Expression and Their Regulation by the Phosphatidylinositol 3'-Kinase/Akt Signaling Pathway
Cancer Res., October 1, 2001; 61(19): 7349 - 7355.
[Abstract] [Full Text] [PDF]

D. A. Elson, G. Thurston, L. E. Huang, D. G. Ginzinger, D. M. McDonald, R. S. Johnson, and J. M. Arbeit
Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1{alpha}
Genes & Dev., October 1, 2001; 15(19): 2520 - 2532.
[Abstract] [Full Text] [PDF]