TY - JOUR
T1 - Three autocrine feedback loops determine HIF1α expression in chronic hypoxia
AU - Qutub, Amina A.
AU - Popel, Aleksander S.
N1 - Funding Information:
This work was supported by NIH 1F32HL085016-01 (A.Q.) and NIH HL079653 and NIH HL087351 (A.S.P.). The authors thank J. Pouyssegur for useful discussion.
PY - 2007/10
Y1 - 2007/10
N2 - Hypoxia occurs in cancer, prolonged exercise, and long-term ischemia with durations of several hours or more, and the hypoxia-inducible factor 1 (HIF1) pathway response to these conditions differs from responses to transient hypoxia. We used computational modeling, validated by experiments, to gain a quantitative, temporal understanding of the mechanisms driving HIF1 response. To test the hypothesis that HIF1α protein levels during chronic hypoxia are tightly regulated by a series of molecular feedbacks, we took into account protein synthesis and product inhibition, and analyzed HIF1 system changes in response to hypoxic exposures beyond 3 to 4 h. We show how three autocrine feedback loops together regulate HIF1α hydroxylation in different microenvironments. Results demonstrate that prolyl hydroxylase, succinate and HIF1α feedback determine intracellular HIF1α levels over the course of hours to days. The model provides quantitative insight critical for characterizing molecular mechanisms underlying a cell's response to long-term hypoxia.
AB - Hypoxia occurs in cancer, prolonged exercise, and long-term ischemia with durations of several hours or more, and the hypoxia-inducible factor 1 (HIF1) pathway response to these conditions differs from responses to transient hypoxia. We used computational modeling, validated by experiments, to gain a quantitative, temporal understanding of the mechanisms driving HIF1 response. To test the hypothesis that HIF1α protein levels during chronic hypoxia are tightly regulated by a series of molecular feedbacks, we took into account protein synthesis and product inhibition, and analyzed HIF1 system changes in response to hypoxic exposures beyond 3 to 4 h. We show how three autocrine feedback loops together regulate HIF1α hydroxylation in different microenvironments. Results demonstrate that prolyl hydroxylase, succinate and HIF1α feedback determine intracellular HIF1α levels over the course of hours to days. The model provides quantitative insight critical for characterizing molecular mechanisms underlying a cell's response to long-term hypoxia.
KW - Angiogenesis
KW - Cancer
KW - Chronic hypoxia
KW - Computational modeling
KW - Ischemia
KW - Prolonged exercise
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U2 - 10.1016/j.bbamcr.2007.07.004
DO - 10.1016/j.bbamcr.2007.07.004
M3 - Article
C2 - 17720260
AN - SCOPUS:34848842419
SN - 0167-4889
VL - 1773
SP - 1511
EP - 1525
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 10
ER -