by Lauren Johnstone
This year the Nobel Prize for Physiology or Medicine was
jointly awarded to William Kaelin of Harvard University, Peter Ratcliffe of
Oxford University, and Gregg Semenza of Johns Hopkins University “for their
discoveries of how cells sense and adapt to oxygen availability”.
It has long been known that oxygen is essential for life,
but oxygen levels can vary as a result of altitude, exercise or disruption in
blood supply caused by disease. Cells have adapted to respond to these changes.
However, the molecular mechanism underlying how cells adapt was previously
unknown before the work of these Nobel Laureates.
The body has many physiological adaptions to hypoxia (low
oxygen levels). One such response is the increase in levels of the hormone
erythropoietin (EPO) which in turn leads to a rise in the production of red
blood cells. In order to gain an understanding of how this process was
regulated by oxygen, Gregg Semenza studied the EPO gene. He was able to
identify a specific region of the gene which was shown to mediate the response
to hypoxia and a protein complex (HIF) which bound to the segment. HIF
(hypoxia-inducible factor) was found to be made up of two transcription factors
(proteins which regulate the rate of transcription of DNA to mRNA), HIF-1α and ARNT. HIF-1α
was found to respond to oxygen levels. At high oxygen levels it was not
present, but at low levels it was. This meant at low oxygen levels
transcription of the EPO gene increased, thus increasing the amount of the
hormone produced.
Ratcliffe and Kaelin identified the VHL protein that is involved
in destroying the HIF-1α
protein at normal oxygen levels. Under normal oxygen levels the HIF-1α protein is modified
by adding hydroxyl groups (this protein modification is called propyl
hydroxylation). This allows VHL to recognise and bind to HIF-1α. The VHL protein is
part of a complex which labels the HIF-1α with ubiquitin, which acts as a tag
marking the protein for degradation in the proteasome.
The molecular switch revealed by these Laureates is
important in helping us to understand and treat a variety of diseases. For
example, the research has implications for patients with diseases where oxygen
is in short supply such as anaemia, heart attacks and strokes.
It also has implications for cancer research and treatment,
as cancer cells have been shown to have increased levels of the HIF-1α
protein in response to low oxygen levels. As a result, drugs that
inhibit that protein can help treat cancer. At present a drug based on the
prizewinning work is already being used to treat some cancers.
Sources:
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