One of the group's most important observations, according to Simon, was finding that reducing oxygen levels to near zero, called anoxia, triggers an entirely different protective response that is independent of the mitochondria. This response involves the enzyme PHD as the oxygen sensor.

"So, now we think we have something for everybody," said Simon. "In oxygen ranges that are moderately low, the mitochondria control the protective response by releasing ROS. But when you get to a really low level of anoxia, the PHD becomes the oxygen sensor." Such a dual-mode mechanism makes evolutionary sense, said Simon, because it enables the cell to adjust to a wide range of low oxygen levels, even the "emergency" created by total oxygen starvation.

The group's findings might also have implications for cancer therapy since tumors use this protective response to thrive in a low-oxygen environment. If one could develop drugs to block that response, it could potentially take away one of the survival strategies exploited by tumors, said the researchers.

Simon said that tumor growth seems to depend on the tumor's ability, via the HIF-triggered machinery, to adapt to low oxygen levels until it can develop its own blood supply. Thus, she said, results from her laboratory are being used as a guide to develop drugs that inhibit HIF in tumors, to render them vulnerable to hypoxia and thwart their ability to grow blood vessels.

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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
7-Jun-2005