HIF at the crossroads between ischemia and carcinogenesis.
Tissue hypoxia occurs where there is an imbalance between oxygen supply and consumption in both, solid tumors as a result of exponential cellular proliferation and in atherosclerotic diseases as a result of inefficient blood supply. Hypoxia-inducible factor 1 (HIF-1) is central in normal angiogenesis and cancer angiogenesis. HIF-1 is a transcriptional activator composed of an O(2)- and growth factor-regulated HIF-1alpha subunit and a constitutively expressed HIF-1beta subunit. Upon activation, HIF-1 drives the expression of genes controlling cell survival and governing the formation of new blood vessels. A better understanding of the regulation of HIF-1alpha levels by the receptor tyrosine kinases/phosphatidylinositol 3-kinase signaling pathway and by the HIF prolyl hydoxylases has provided new insights into the development of anticancer and revascularization therapeutics. We will focus on the potential of a new pharmacology for regulating HIF pathways in both, cancer and ischemic cardiac diseases. The consequences of the switch of HIF activation in these two disease states and the signaling pathway overlap that atherosclerosis and cancer angiogenesis share are discussed.
Paul
Stefan A M
SA
Department of Internal Medicine I, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Simons
Jonathan W
JW
Mabjeesh
Nicola J
NJ
D000818:Animals; D001161:Arteriosclerosis / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000503:physiopathology / Q000628:therapy; D015687:Cell Hypoxia; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007511:Ischemia / Q000503:physiopathology; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors