Overview of HIF-1 Signaling

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Hypoxia is defined as a deficiency in the supply of oxygen available to a tissue1. This often occurs under pathogenic conditions and contributes to the progression of disease. Cancer and other inflammatory conditions such as inflammatory bowel disease and acute lung injury are diseases where initial inflammation leads to hypoxic conditions; ischemia and reperfusion injury, such as after a heart attack, is conversely characterized by a persistent lack of oxygen2. In an attempt to mitigate the adverse effects of oxygen deprivation, hypoxic conditions activate the hypoxia-inducible factors, or HIF proteins, which regulate oxygen homeostasis in cells.

 

HIF-1 is a transcription factor that controls the body’s response to low oxygen conditions by binding to hypoxia response elements in a variety of genes3. The protein is a heterodimer comprised of HIF-1a and HIF-1b; their expression at the RNA and protein levels are induced in cells exposed the hypoxic condition of 1% oxygen. The protein is degraded at physiological oxygen concentrations of 20%4,5 after ubiquitination and targeting to the proteasome6.

 

HIF-1 promotes both angiogenesis and anaerobic metabolism to maintain tissue homeostasis under low oxygen conditions. VEGF and iNOS, which promote angiogenesis, are under the transcriptional control of HIF-17. By promoting increased blood flow to tissue, HIF-1 increases the likelihood of oxygen reaching the hypoxic tissue and reversing the low oxygen state. HIF-1 also controls the transcriptional expression of numerous genes involved in metabolism. Expression of HIF-1 both upregulates the expression of genes required for glycolysis8 and downregulates genes involved in regulating oxygen consumption in the mitochondria9. This allows cells to utilize glucose instead of oxygen to generate energy in the form of ATP while oxygen is lacking10.

 

Upregulation of HIF-1 can either promote or protect against disease11. The von Hippel-Lindau factor, a component of the ubiquitin ligase involved in targeting HIF-1 to the proteasome for degradation, is often mutated in cancer12. This maintains an increased state of anaerobic respiration, or glycolysis6 – known as the Warburg Effect13 –  and has been shown to promote tumor progression. Expression of HIF-1 in tumors promotes epithelial-to-mesenchymal transition and metastasis in a variety of cancers, including breast cancer, colorectal cancer, liver cancer, head and neck cancer, and renal cell carcinoma14–17. HIF-1 is also involved in cardiovascular disease, including protecting against tissue damage following ischemia and heart failure, through maintenance of tissue homeostasis3. HIF-1 promotes expression of both adenosine and its receptor A2BAR, which have been shown to be required for protection of cardiac tissue during hypoxia18.

 

Finally, HIF-1 is involved in the immune response at both the cellular and tissue levels. Under hypoxic conditions, upregulation of HIF-1 negatively regulates Type-1 T helper cell function through a positive feedback loop that suppresses IFNg production in conjunction with upregulated STAT3 and IL-10 expression19. At the tissue level, aberrant expression of HIF-1 has been implicated in a number of autoimmune diseases, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease20. Similarly, suppression of HIF-1 was shown to protect against tissue damage following bacterial infection, suggesting a possible therapeutic modality to improve patient survival.

 

Detection of human HIF1-alpha (red) in HepG2 cells treated with (left) and without cobalt chloride (right) by ICC-IF

Detection of human HIF1-alpha (red) in HepG2 cells treated with (left) and without cobalt chloride (right) by ICC-IF. Antibody: Rabbit anti-HIF1-alpha recombinant monoclonal antibody [BL-124-3F7] (A700-001). Secondary: DyLight® 594-conjugated goat anti-rabbit IgG (A120-201D4). Counterstain: DAPI (blue).

Detection of human AKT2 by WB

Detection of human AKT2 by WB of HeLa, 293T, and Jurkat lysate.  Antibody: Rabbit anti-AKT2 (A302-209A).  Secondary: HRP-conjugated goat anti-rabbit IgG (A120-101P).

 

Below is the entire list of targets involved in HIF-1 Signaling research. Can’t find what you are looking for? Bethyl offers a custom antibody service.

 

References

1. Cafaro RP. 1960. Hypoxia: Its Causes and Symptoms. J. Am. Dent. Soc. Anesthesiol. Apr;7(4):4–8.

2. Bartels K, Grenz A, Eltzschig HK. 2013. Hypoxia and inflammation are two sides of the same coin. Proc. Natl. Acad. Sci. U. S. A. Nov 12;110(46):18351–2.

3. Semenza GL. 2014. Hypoxia-inducible factor 1 and cardiovascular disease. Annu. Rev. Physiol. 76:39–56.

4. Atkuri KR, Herzenberg LA, Niemi A-K, et al. 2007. Importance of culturing primary lymphocytes at physiological oxygen levels. Proc. Natl. Acad. Sci. U. S. A. March 13;104(11):4547–4552.

5. Wang GL, Jiang BH, Rue EA, Semenza GL. 1995. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. U. S. A. June 6;92(12):5510–5514.

6. Kaelin WG, Ratcliffe PJ. 2008. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell May 23;30(4):393–402.

7. Büchler P, Reber HA, Büchler M, et al. 2003. Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer. Jan;Pancreas 26(1):56–64.

8. Marín-Hernández A, Gallardo-Pérez JC, Ralph SJ, et al. 2009. HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev. Med. Chem. Aug 9;9(9):1084–1101.

9. Papandreou I, Cairns RA, Fontana L, et al. 2006. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption Mar;3(3):187–197.

10. Zheng J. 2012. Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). Oncol. Lett. Dec;4(6):1151–1157.

11. Semenza GL. 2000. HIF-1 and human disease: one highly involved factor. Genes Dev. Aug 15;14(16):1983–1991.

12. Gossage L, Eisen T, Maher ER. 2015. VHL, the story of a tumour suppressor gene. Nat. Rev. Cancer Jan;15(1):55–64.

13. Liberti M V., Locasale JW. 2016. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem. Sci. Mar;41(3):211–218.

14. Zhang W, Shi X, Peng Y, et al. 2015. HIF-1α Promotes Epithelial-Mesenchymal Transition and Metastasis through Direct Regulation of ZEB1 in Colorectal Cancer. PLoS One June 9;10(6):e0129603.

15. Liu Z-J, Semenza GL, Zhang H-F. 2015. Hypoxia-inducible factor 1 and breast cancer metastasis. J. Zhejiang Univ. Sci. B Jan;16(1):32–43.

16. Rankin EB, Giaccia AJ. 2016. Hypoxic control of metastasis. Science April 8;352(6282):175–180.

17. Cheng S, Han L, Guo J, et al. 2014. The essential roles of CCR7 in epithelial-to-mesenchymal transition induced by hypoxia in epithelial ovarian carcinomas. Tumour Biol. Dec;35(12):12293–12298.

18. Eckle T, Kohler D, Lehmann R, et al. 2008. Hypoxia-Inducible Factor-1 Is Central to Cardioprotection: A New Paradigm for Ischemic Preconditioning Jul 8;118(2):166–175.

19. Shehade H, Acolty V, Moser M, Oldenhove G. 2015. Cutting Edge: Hypoxia-Inducible Factor 1 Negatively Regulates Th1 Function. J. Immunol. Aug 15;195(4):1372–1376.

20. Deng W, Feng X, Li X, et al. 2016. Hypoxia-inducible factor 1 in autoimmune diseases. Cell. Immunol. May;303:7–15.