Gregg Semenza, MD, Ph.D., and Stylianos Antonarakis, MDDCh, identified two enhancers - DNA sequences near genes that bind proteins to help control the gene - that work specifically when oxygen is low. The other enhancers were found on either side of the gene for erythropoietin, a hormone that signals for more red blood cells to be made. Once enhancer turns the gene on in the kidneys and the other in the liver.

Hypoxia is a condition when the body’s cells are deprived of oxygen. Gregg Semenza, MD, PhD, and Guang Wong, Ph.D., aptly named the protein that binds the enhancers of the erythropoietin gene in response to low oxygen hypoxia inducible factor 1 (HIF-1).

HIF-1 protein levels increased when oxygen levels were reduced in all mammalian cell lines tested, suggesting that turning up HIF-1 levels may be a universal response to hypoxia.

The Semenza lab discovered that HIF-1 turns on the gene for VEGF, which controls vascularization--the production of new blood vessels. Vascularization is important for healing during an injury, but it is also required for tumors to grow and spread throughout the body.

HIF-1 is found to turn on an oncogene—a gene that when dysregulated leads to development of cancer. This provides the first evidence that cancer cells need HIF-1 to adapt to low oxygen environments.

The Semenza lab shows that HIF-1 is essential for survival of mouse embryos. Without HIF-1, the heart, blood vessels and blood don’t develop.

HIF-1 is found to be highly expressed in many human cancers. This suggests that inhibiting HIF-1 may be a potential therapeutic for the treatment of cancer.

Turning on extra HIF-1 with chemicals reduces the amount of damaged tissue in the brains of mice that have had strokes. This suggests therapeutics may be developed that can reduce the damage left by strokes.

Injecting a virus engineered to make HIF-1 causes blood vessels to grow in mice. This suggests that increasing HIF-1 levels may be useful in patients with coronary artery disease or leg circulation problems.

Hopkins researchers report that inherited differences in the gene for HIF-1 influence the body’s response to coronary artery disease.

Semenza’s team discovers that two drugs, digoxin and acriflavine, block HIF-1 from making VEGF and other proteins that are necessary for tumor growth in animal models. Both drugs have been used in the past for other purposes and can now be tested in cancer patients.

If blood supply is restricted, tissue damage occurs. One of the consequences of aging and diabetes is poor circulation. Semenza’s team treated diabetic mice with HIF-1 gene therapy, which helped improve blood flow to their limbs and prevented tissue damage. In a separate experiment they combined HIF-1 gene therapy with blood stem cells to improve circulation in very old mice and prevent limb loss.

Semenza’s team found that a common chemotherapy drug caused triple-negative breast cancer cells to thrive by dialing up levels of HIF. The good news was that treating mice with a combination of a HIF inhibitor and chemotherapy shrank their triple-negative tumors by 30 percent more than treatment with paclitaxel alone.