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Gene Review

Hif1a  -  hypoxia inducible factor 1, alpha subunit

Mus musculus

Synonyms: AA959795, ARNT-interacting protein, HIF-1-alpha, HIF-1alpha, HIF1-alpha, ...
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Disease relevance of Hif1a

  • In contrast, prior chronic hypoxia resulted in a diminished ventilatory response to acute hypoxia in Hif1a(+/-) mice [1].
  • Similar to our laboratory's previous results, hypoxia-induced right ventricular hypertrophy and polycythemia were blunted in Hif1a(+/-) mice [2].
  • In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1alpha (Hif-1alpha) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia [3].
  • In cardiac hypertrophy, it has been suggested that the myocardium becomes hypoxic, increasing HIF-1alpha stabilization and inducing coronary neovascularization, however, this mechanism has not been demonstrated in vivo [4].
  • Reverse transcription PCR analysis of total RNA derived from normoxic and hypoxic mouse hepatoma and fibroblast cell lines suggested that the two alternative mRNA isoforms are constitutively coexpressed in these cells, and that two different promoters drive transcription of HIF-1alpha [5].
  • Growth factor-dependent HIF-1alpha expression reprograms the intracellular fate of glucose, resulting in decreased glucose-dependent anabolic synthesis and increased lactate production, an effect that is enhanced when HIF-1alpha protein is stabilized by hypoxia [6].
  • We determine that SENP1 controls Epo production by regulating the stability of hypoxia-inducible factor 1alpha (HIF1alpha) during hypoxia [7].
  • Real-time PCR confirmed these results, showing higher expression of proapoptotic protein phosphatase 2a (PP2A) and lower expression of anti-apoptotic B-cell leukemia/lymphoma 2 (BCL2) in HIF-1alpha+/+ calluses [8].

High impact information on Hif1a

  • Here, we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF-1alpha, its negative regulator VHL, and a known downstream target, VEGF [9].
  • Our results show that HIF-1alpha is essential for the regulation of glycolytic capacity in myeloid cells: when HIF-1alpha is absent, the cellular ATP pool is drastically reduced [9].
  • Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis [10].
  • As hypoxic stress contributes to many (patho)biological disorders, this new role for HIF-1alpha in hypoxic control of cell growth and death may be of general pathophysiological importance [10].
  • ARNT forms heterodimeric complexes with the arylhydrocarbon receptor, HIF-1alpha, Sim and the PAS protein Per [11].

Chemical compound and disease context of Hif1a


Biological context of Hif1a

  • Hif1a-/- mouse embryos with complete deficiency of HIF-1alpha due to homozygosity for a null allele at the Hif1a locus die at midgestation, with multiple cardiovascular malformations and mesenchymal cell death [17].
  • Hif1a+/- heterozygotes develop normally and are indistinguishable from Hif1a+/+ wild-type littermates when maintained under normoxic conditions [17].
  • We also sequenced Hif1a exon I.1 and flanking regions, and mapped a single exon I.1 transcription initiation site [5].
  • The impact of IH on serum TG levels in WT mice was significantly greater than that in Hif1a(+/-) mice (95 +/- 9 vs. 66 +/- 6 mg/dl, P < 0.05), whereas cholesterol and glucose levels were affected independently of genotype [18].
  • Nonbiased stereological cell counts of TH-positive neurons in SN of young adult HIF-1alpha CKO mice revealed a reduction of 31% compared with cre/wt mice (in which the wild-type Hif1a allele is expressed in parallel with the Cre recombinase allele) [19].

Anatomical context of Hif1a

  • In this work, we show that cAMP transcriptionally activates Hif1a gene in a melanocyte cell-specific manner and increases the expression of a functional hypoxia-inducible factor 1alpha (HIF1alpha) protein resulting in a stimulation of Vegf expression [20].
  • Histologic analysis revealed no abnormalities of carotid body morphology in Hif1a(+/-) mice [1].
  • Although the ventilatory response to acute hypoxia was not impaired in Hif1a(+/-) mice, the response was primarily mediated via vagal afferents, whereas in wild-type mice, carotid body chemoreceptors played a predominant role [1].
  • HIF-1alpha null mutant embryos exhibit clear morphological differences by embryonic day (E) 8.0, and by E8.5 there is a complete lack of cephalic vascularization, a reduction in the number of somites, abnormal neural fold formation and a greatly increased degree of hypoxia (measured by the nitroimidazole EF5) [21].
  • Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction [22].

Associations of Hif1a with chemical compounds

  • In this study, the physiological responses of Hif1a+/- and Hif1a+/+ mice exposed to 10% O2 for one to six weeks were analyzed [17].
  • In tissue culture cells, VEGF mRNA expression was induced by glucose deprivation independent of HIF-1alpha, providing a mechanism for increased VEGF mRNA expression in Hif1a-/- embryos, in which absence of adequate tissue perfusion resulted in both O2 and glucose deprivation [23].
  • We found that constitutive activity of Hif-1alpha resulted in diminished Ca(2+) response upon TCR crosslinking despite equivalent activation of phospholipase C(gamma1), normal intracellular Ca(2+) stores, and normal entry of Ca(2+) across the plasma membrane [22].
  • We also found that basal threonine and tyrosine phosphorylation (within the TEY motif) of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the corresponding ERK1/2 activity were defective in hypoxic HIF-1 alpha-null mEFs but not in wild-type mEFs, independently of glucose uptake [24].
  • Insulin treatment fails to inactivate proline hydroxylation of HIF-1alpha, which triggers recruitment of the von Hippel-Lindau protein and oxygen-dependent degradation of HIF-1alpha [25].

Physical interactions of Hif1a

  • Conversely, a constitutively active Akt oncogene stabilized HIF-1alpha under normoxia independently of prolyl hydroxylation, suggesting an alternative mechanism for HIF-1alpha stabilization [14].
  • Formation of neural ARNT2/HIF-1alpha complexes in Arnt(-/-) ES cell-derived teratocarcinomas may explain why these tumors express VEGF, vascularize and grow efficiently, in contrast to ARNT-deficient hepatomas [26].
  • It is concluded that seal HIF-1alpha may act as a transcriptional activator and that its presence in seal tissues is probably not caused by its inability to interact with pVHL [27].

Regulatory relationships of Hif1a

  • Our results demonstrate that CT-1 expression in ES cells is regulated by ROS and HIF-1alpha and imply a crucial role of CT-1 in the survival and proliferation of ES-cell-derived cardiac cells [12].
  • These and other data indicate that HIF-2alpha promotes tumor growth more effectively than HIF-1alpha in multiple contexts [28].
  • In both cell types, loss of HIF-1alpha abolished hypoxia-induced growth arrest and did this in a p53-independent fashion [29].
  • Oncogenic ras upregulates the expression of VEGF through the activation of the transcriptional enhancer hypoxia inducible factor-1alpha (HIF-1alpha) by a still poorly understood mechanism [30].
  • Hypoxia increased nuclear accumulation of HIF-1alpha and activated the Sox9 promoter [31].
  • This work establishes for the first time HIF1alpha as a key component in the genetic program that regulates chondrogenesis by regulating Sox9 expression in hypoxic prechondrogenic cells [32].
  • Under conditions of hypoxia, hypoxia-inducible factor-1alpha (HIF-1alpha) suppresses transcription of LIF-specific receptor (LIFR) by directly binding to the reverse hypoxia-responsive element located in the LIFR promoter [33].

Other interactions of Hif1a


Analytical, diagnostic and therapeutic context of Hif1a


  1. Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha. Kline, D.D., Peng, Y.J., Manalo, D.J., Semenza, G.L., Prabhakar, N.R. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  2. Partial HIF-1alpha deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia. Shimoda, L.A., Manalo, D.J., Sham, J.S., Semenza, G.L., Sylvester, J.T. Am. J. Physiol. Lung Cell Mol. Physiol. (2001) [Pubmed]
  3. Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice. Rankin, E.B., Higgins, D.F., Walisser, J.A., Johnson, R.S., Bradfield, C.A., Haase, V.H. Mol. Cell. Biol. (2005) [Pubmed]
  4. Aryl hydrocarbon receptor null mice develop cardiac hypertrophy and increased hypoxia-inducible factor-1alpha in the absence of cardiac hypoxia. Thackaberry, E.A., Gabaldon, D.M., Walker, M.K., Smith, S.M. Cardiovasc. Toxicol. (2002) [Pubmed]
  5. The mouse gene for hypoxia-inducible factor-1alpha--genomic organization, expression and characterization of an alternative first exon and 5' flanking sequence. Wenger, R.H., Rolfs, A., Kvietikova, I., Spielmann, P., Zimmermann, D.R., Gassmann, M. Eur. J. Biochem. (1997) [Pubmed]
  6. The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Lum, J.J., Bui, T., Gruber, M., Gordan, J.D., DeBerardinis, R.J., Covello, K.L., Simon, M.C., Thompson, C.B. Genes Dev. (2007) [Pubmed]
  7. SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cheng, J., Kang, X., Zhang, S., Yeh, E.T. Cell (2007) [Pubmed]
  8. Enhanced bone regeneration associated with decreased apoptosis in mice with partial HIF-1alpha deficiency. Komatsu, D.E., Bosch-Marce, M., Semenza, G.L., Hadjiargyrou, M. J. Bone Miner. Res. (2007) [Pubmed]
  9. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cramer, T., Yamanishi, Y., Clausen, B.E., Förster, I., Pawlinski, R., Mackman, N., Haase, V.H., Jaenisch, R., Corr, M., Nizet, V., Firestein, G.S., Gerber, H.P., Ferrara, N., Johnson, R.S. Cell (2003) [Pubmed]
  10. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Carmeliet, P., Dor, Y., Herbert, J.M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Bono, F., Abramovitch, R., Maxwell, P., Koch, C.J., Ratcliffe, P., Moons, L., Jain, R.K., Collen, D., Keshert, E., Keshet, E. Nature (1998) [Pubmed]
  11. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Maltepe, E., Schmidt, J.V., Baunoch, D., Bradfield, C.A., Simon, M.C. Nature (1997) [Pubmed]
  12. Regulation of cardiotrophin-1 expression in mouse embryonic stem cells by HIF-1alpha and intracellular reactive oxygen species. Ateghang, B., Wartenberg, M., Gassmann, M., Sauer, H. J. Cell. Sci. (2006) [Pubmed]
  13. Mouse hypoxia-inducible factor-1alpha is encoded by two different mRNA isoforms: expression from a tissue-specific and a housekeeping-type promoter. Wenger, R.H., Rolfs, A., Spielmann, P., Zimmermann, D.R., Gassmann, M. Blood (1998) [Pubmed]
  14. Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha. Chan, D.A., Sutphin, P.D., Denko, N.C., Giaccia, A.J. J. Biol. Chem. (2002) [Pubmed]
  15. Nelfinavir Down-regulates Hypoxia-Inducible Factor 1{alpha} and VEGF Expression and Increases Tumor Oxygenation: Implications for Radiotherapy. Pore, N., Gupta, A.K., Cerniglia, G.J., Jiang, Z., Bernhard, E.J., Evans, S.M., Koch, C.J., Hahn, S.M., Maity, A. Cancer Res. (2006) [Pubmed]
  16. The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Unruh, A., Ressel, A., Mohamed, H.G., Johnson, R.S., Nadrowitz, R., Richter, E., Katschinski, D.M., Wenger, R.H. Oncogene (2003) [Pubmed]
  17. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. Yu, A.Y., Shimoda, L.A., Iyer, N.V., Huso, D.L., Sun, X., McWilliams, R., Beaty, T., Sham, J.S., Wiener, C.M., Sylvester, J.T., Semenza, G.L. J. Clin. Invest. (1999) [Pubmed]
  18. Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1alpha. Li, J., Bosch-Marce, M., Nanayakkara, A., Savransky, V., Fried, S.K., Semenza, G.L., Polotsky, V.Y. Physiol. Genomics (2006) [Pubmed]
  19. Lack of hypoxia-inducible factor-1alpha impairs midbrain neural precursor cells involving vascular endothelial growth factor signaling. Milosevic, J., Maisel, M., Wegner, F., Leuchtenberger, J., Wenger, R.H., Gerlach, M., Storch, A., Schwarz, J. J. Neurosci. (2007) [Pubmed]
  20. Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells. Buscà, R., Berra, E., Gaggioli, C., Khaled, M., Bille, K., Marchetti, B., Thyss, R., Fitsialos, G., Larribère, L., Bertolotto, C., Virolle, T., Barbry, P., Pouysségur, J., Ponzio, G., Ballotti, R. J. Cell Biol. (2005) [Pubmed]
  21. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. Ryan, H.E., Lo, J., Johnson, R.S. EMBO J. (1998) [Pubmed]
  22. Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. Neumann, A.K., Yang, J., Biju, M.P., Joseph, S.K., Johnson, R.S., Haase, V.H., Freedman, B.D., Turka, L.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  23. Defective vascularization of HIF-1alpha-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Kotch, L.E., Iyer, N.V., Laughner, E., Semenza, G.L. Dev. Biol. (1999) [Pubmed]
  24. Glucose utilization is essential for hypoxia-inducible factor 1 alpha-dependent phosphorylation of c-Jun. Laderoute, K.R., Calaoagan, J.M., Knapp, M., Johnson, R.S. Mol. Cell. Biol. (2004) [Pubmed]
  25. Insulin and hypoxia share common target genes but not the hypoxia-inducible factor-1alpha. Yim, S., Choi, S.M., Choi, Y., Lee, N., Chung, J., Park, H. J. Biol. Chem. (2003) [Pubmed]
  26. The role of ARNT2 in tumor angiogenesis and the neural response to hypoxia. Maltepe, E., Keith, B., Arsham, A.M., Brorson, J.R., Simon, M.C. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  27. Hypoxia-inducible factor 1 proteomics and diving adaptations in ringed seal. Johnson, P., Elsner, R., Zenteno-Savín, T. Free Radic. Biol. Med. (2005) [Pubmed]
  28. Targeted replacement of hypoxia-inducible factor-1alpha by a hypoxia-inducible factor-2alpha knock-in allele promotes tumor growth. Covello, K.L., Simon, M.C., Keith, B. Cancer Res. (2005) [Pubmed]
  29. Hypoxia-inducible factor 1alpha is essential for cell cycle arrest during hypoxia. Goda, N., Ryan, H.E., Khadivi, B., McNulty, W., Rickert, R.C., Johnson, R.S. Mol. Cell. Biol. (2003) [Pubmed]
  30. MAPK and Akt act cooperatively but independently on hypoxia inducible factor-1alpha in rasV12 upregulation of VEGF. Sodhi, A., Montaner, S., Miyazaki, H., Gutkind, J.S. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  31. Hypoxia induces chondrocyte-specific gene expression in mesenchymal cells in association with transcriptional activation of Sox9. Robins, J.C., Akeno, N., Mukherjee, A., Dalal, R.R., Aronow, B.J., Koopman, P., Clemens, T.L. Bone (2005) [Pubmed]
  32. HIF1alpha regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis. Amarilio, R., Viukov, S.V., Sharir, A., Eshkar-Oren, I., Johnson, R.S., Zelzer, E. Development (2007) [Pubmed]
  33. Hypoxia-inducible factor-1 alpha inhibits self-renewal of mouse embryonic stem cells in Vitro via negative regulation of the leukemia inhibitory factor-STAT3 pathway. Jeong, C.H., Lee, H.J., Cha, J.H., Kim, J.H., Kim, K.R., Kim, J.H., Yoon, D.K., Kim, K.W. J. Biol. Chem. (2007) [Pubmed]
  34. VEGFA is necessary for chondrocyte survival during bone development. Zelzer, E., Mamluk, R., Ferrara, N., Johnson, R.S., Schipani, E., Olsen, B.R. Development (2004) [Pubmed]
  35. Hypoxia-inducible factor-1 deficiency results in dysregulated erythropoiesis signaling and iron homeostasis in mouse development. Yoon, D., Pastore, Y.D., Divoky, V., Liu, E., Mlodnicka, A.E., Rainey, K., Ponka, P., Semenza, G.L., Schumacher, A., Prchal, J.T. J. Biol. Chem. (2006) [Pubmed]
  36. Conditional disruption of the aryl hydrocarbon receptor nuclear translocator (Arnt) gene leads to loss of target gene induction by the aryl hydrocarbon receptor and hypoxia-inducible factor 1alpha. Tomita, S., Sinal, C.J., Yim, S.H., Gonzalez, F.J. Mol. Endocrinol. (2000) [Pubmed]
  37. Neuroprotection by hypoxic preconditioning involves oxidative stress-mediated expression of hypoxia-inducible factor and erythropoietin. Liu, J., Narasimhan, P., Yu, F., Chan, P.H. Stroke (2005) [Pubmed]
  38. Regulation of the hypoxia-inducible factor-1 alpha. ARNT is not necessary for hypoxic induction of HIF-1 alpha in the nucleus. Gassmann, M., Chilov, D., Wenger, R.H. Adv. Exp. Med. Biol. (2000) [Pubmed]
  39. HIF-1alpha expression regulates the bactericidal capacity of phagocytes. Peyssonnaux, C., Datta, V., Cramer, T., Doedens, A., Theodorakis, E.A., Gallo, R.L., Hurtado-Ziola, N., Nizet, V., Johnson, R.S. J. Clin. Invest. (2005) [Pubmed]
  40. Podocyte expression of hypoxia-inducible factor (HIF)-1 and HIF-2 during glomerular development. Freeburg, P.B., Robert, B., St John, P.L., Abrahamson, D.R. J. Am. Soc. Nephrol. (2003) [Pubmed]
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