What is Hypoxia-Inducible Factor?

By Sarah MooreReviewed by Michael Greenwood, M.Sc.

Hypoxia-inducible factor is a type of transcription factor that responds to the changing level of oxygen supply to the cell. The discovery of how it functions in the body to allow cells to respond to low oxygen levels has added a profound layer of understanding to how the body evolved this crucial capability. Further studies have elucidated the role of hypoxia-inducible factors in illness, such as anemia, cancer, and neurological disorders.

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A Nobel Prize-winning discovery

Oxygen is certainly critical to maintaining animal life; however, the mechanisms that allow cells to adapt to changes in oxygen levels have only recently been elucidated. In 2019, William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza won the Nobel Prize in Physiology or Medicine for their discovery of how cells both sense and adapt to the dynamic nature of oxygen availability.

Evolution has seen animals developing systems to supply oxygen to tissues and cells, ensuring that it is available to the mitochondria for fueling the process of converting food into useable energy. Corneille Heymans, back in the 1930s, discovered that the carotid bodies are responsible for sensing blood oxygen levels to modulate our respiratory rates by communicating this information to the brain.

This understanding of how the body responds to oxygen levels has since been developed further. Since the beginning of the 20th century, scientists had been aware of the role of the hormone erythropoietin (EPO) in increasing levels of red blood cells (erythropoiesis) in response to hypoxia. However, it wasn't until the work of the Nobel Prize-winning team that the mystery of the underlying mechanism that allows oxygen to control this was solved.

Gregg Semenza cultivated liver cells and discovered that a protein complex, which he named the hypoxia-inducible factor (HIF), bound itself to the identified DNA segment in an oxygen-dependent manner. Later studies revealed that HIF comprises two specific transcription factors (DNA-binding proteins), known as HIF-1α and ARNT.

Studies uncovered that there is a low level of HIF-1α present in a cell in the scenario where oxygen levels are high. Conversely, when oxygen levels are low, the level of HIF-1α increases. This increase sees HIF-1α regulating the EPO gene by binding with it, along with other genes.

During hypoxia, the degradation of HIF-1α is prevented, but as oxygen levels return to normal, HIF-1α begins to be broken down by the proteasome. In this scenario, ubiquitin binds with the HIF-1α protein and tags it for targeting by degradation proteins in the proteasome.

The oxygen-dependent behavior of this binding of ubiquitin to HIF-1α remained elusive until Semenza, Ratcliffe, and William Kaelin Jr. came across the answer whilst investigating von Hippel-Lindau's disease (VHL disease), which is related to several types of cancer. During their investigations, they discovered that the VHL gene encodes for a protein that plays a role in preventing the initiation of cancer.

These cancer cells without a functional VHL gene also had high levels of hypoxia-regulated genes. Introducing the VHL gene into these cells had the impact of returning these levels to normal. Clearly, VHL is fundamental to controlling responses to hypoxia, but the researchers weren't sure how. The team then saw that VHL was physically interacting with HIF-1α, and its presence was necessary for HIF-1α's degradation at normal oxygen levels.

The final step was of gaining insight into how oxygen levels regulate the interaction between VHL and HIF-1α. At the time, it was already known that hydroxyl groups are added on to HIF-1α at two specific locations under normal oxygen levels. The mechanism explains how oxygen-sensitive enzymes and normal oxygen levels regulate the degradation of HIF-1α.

The specific enzymes involved (prolyl hydroxylases) were subsequently identified by Ratcliffe. It was concluded that HIF-1α's gene activating function was controlled by oxygen-dependent hydroxylation, a finding that won the team the Nobel Prize for uncovering how the oxygen sensing mechanism functions.

HIF as a therapeutic target

The role of HIF has been implied in various illnesses:

Anemia

Recent studies have highlighted the hypoxia-inducible factor as a potential therapeutic target for anemia. Within the past year, clinical trials have demonstrated the effectiveness of HIF stabilizers in increasing hemoglobin levels of both nondialysis and dialysis CKD patients. The results are promising as so far, treatment has not been linked with serious adverse effects.

Cancer

Numerous studies have elucidated the role of HIF-1α in various cancers, making it an attractive potential target for new therapies. Research has shown that there is a relationship between increased levels of HIF-1α and factors such as tumor metastasis, angiogenesis, and poor patient prognosis. The HIF-1α pathway has been identified as a crucial survival pathway, and new studies are looking into novel therapies that could exploit this pathway.

Neurology

HIF-1α activity is unusual in numerous neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's diseases (HD), and amyotrophic lateral sclerosis (ALS). This has made the transcription factor a potential medicinal target for the development of new treatments.

The discovery of the hypoxia-inducible factor's role in responding to changing cellular oxygen levels has been significant in understanding related, critical mechanisms. Through this discovery, the relationship observed between hypoxia-inducible factors and various illnesses may lead to the development of new, effective therapies.

Further Reading

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