Why the Lasker Awards are So Important This Year;

It’s All About the Oxygen

The Lasker Awards were won this year by a trio of incredibly important figures in physiologic oxygen research; William Kaelin, Peter Ratcliffe, and Gregg Semenza.

 

What did they do?

These three researchers, along with others, have traced the molecular mechanisms that connect changes in oxygen levels to cellular responses.

 Gregg Semenza, along with his post-doc, Guang Wang, first reported the structure of a protein that was regulated by oxygen levels [1]. They called it Hypoxia-inducible factor 1 (HIF-1). It had two subunits, alpha and beta. The beta subunit was expressed all the time, but the alpha subunit changed in levels when oxygen levels changed.

 

Working with Peter Ratcliffe, who was studying hypoxia-induced genes in the drosophila model [2], Semenza’s group identified many, many genes downstream of HIF-1 signaling. William Kaelin’s work, on a factor that is disrupted in von Hippel-Lindau disease (VHL), provided a critical piece of the HIF-1 signaling pathway puzzle [3].

Together, these researchers, and the other researchers in their labs, showed that when oxygen levels fall, oxygen-sensitive prolylhydroxylases (PHD) modify VHL which in turn, stabilizes HIF-1 alpha levels, activating large sets of genes that change cell behavior.

 

What does HIF-1 do?

HIF-1 alpha stabilization unlocks whole sets of genes responsible for stimulating the development of new red blood cells or the growth of new blood vessels to feed oxygen-starved tissues. When oxygen levels rise, these same mechanisms can help stop the overgrowth of blood vessels.

However, HIF 1-alpha regulation turns out to be incredibly important to processes far beyond red blood cell and blood vessel generation. HIF 1-alpha is key to inflammatory signaling in normal immune function [4] [5] and disease states such as rheumatoid arthritis [6]. It is critically important to ischemia/reperfusion injury which is the response of tissues to recovery from stroke or heart attack.  It also is key to the lack of interaction between tumor cells and their environment [7, 8]. It is an incredibly important factor in the etiology of retinal diseases [9]. Extracellular matrix remodeling under low oxygen is mediated by HIF-1 [10]. Also all types of stem cells use HIF-1 to change their proliferation and differentiation rates in response to changes in oxygen levels [11] [12].

 

Why is this important?

This work has given us a multitude of new therapeutic targets [13]. Among these opportunities, the ability to keep tumors from growing new blood vessels would help control the ability of tumors to grow large or metastasize effectively. The role of HIF-1 in mediating a tumor’s responses to radiation may also be enhanced [14]. Wound healing may be improved by modifying HIF responses [15]. Limiting ischemia/reperfusion injury in stroke and cardiac patients is a huge opportunity for HIF-1-specific agents. Also, the ability to keep stem cells growing when we want them to grow, and differentiating in directions that we want to them to differentiate may be enhanced by targeting HIF-1.

This is not an exhaustive list, but a taste of the potential benefits that the body of work from these three researchers may produce as biomedical research moves forward. That’s why it is so important to recognize them and all the others that have contributed to our current understanding of HIF-1.

 

 

1. Wang, G.L., et al., Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A, 1995. 92.

2. Nagao, M., et al., Drosophila melanogaster SL2 cells contain a hypoxically inducible DNA binding complex which recognises mammalian HIF-binding sites. FEBS Lett, 1996. 387(2-3): p. 161-6.

3. Ivan, M., et al., HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science, 2001. 292(5516): p. 464-8.

4. Shengwei, H., et al., Crosstalk between the HIF-1 and toll-like receptor/nuclear factor-kappaB pathways in the oral squamous cell carcinoma microenvironment. Oncotarget, 2016.

5. Thompson, A.A., et al., Hypoxia, the HIF pathway and neutrophilic inflammatory responses. Biol Chem, 2013. 394(4): p. 471-7.

6. Fearon, U., et al., Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Nat Rev Rheumatol, 2016. 12(7): p. 385-397.

7. Semenza, G.L., HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest, 2013. 123(9): p. 3664-71.

8. LaGory, E.L. and A.J. Giaccia, The ever-expanding role of HIF in tumour and stromal biology. Nat Cell Biol, 2016. 18(4): p. 356-365.

9. Hoppe, G., et al., Comparative systems pharmacology of HIF stabilization in the prevention of retinopathy of prematurity. Proceedings of the National Academy of Sciences, 2016. 113(18): p. E2516-E2525.

10. Gilkes, D.M., et al., Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts. J Biol Chem, 2013. 288(15): p. 10819-29.

11. Palomaki, S., et al., HIF-1alpha is upregulated in human mesenchymal stem cells. Stem Cells, 2013. 31(9): p. 1902-9.

12. Imanirad, P. and E. Dzierzak, Hypoxia and HIFs in regulating the development of the hematopoietic system. Blood Cells Mol Dis, 2013. 51(4): p. 256-63.

13. Takubo, K. and T. Suda, Opening the door for HIF1alpha tuning. Blood, 2014. 123(2): p. 151-2.

14. Meijer, T.W., et al., Targeting hypoxia, HIF-1, and tumor glucose metabolism to improve radiotherapy efficacy. Clin Cancer Res, 2012. 18(20): p. 5585-94.

15. Du, J., et al., Combination of HIF-1alpha gene transfection and HIF-1-activated bone marrow-derived angiogenic cell infusion improves burn wound healing in aged mice. Gene Ther, 2013. 20(11): p. 1070-6.