[Adaptation to chronic hypoxia: gene regulation and drug development]

Along with the changes of environmental and/or microenvironmental conditions, organs and cells in our body are frequently exposed to hypoxia. Hypoxic response, which is activated under such condition, controls metabolism, respiration and so on to maintain homeostasis. Hypoxia-Inducible Factor (HIF) is a transcription factor which plays a key role during this response. HIF-1 is upregulated in response to hypoxia, however, we identified that it is downregulated during prolonged hypoxia. We defined this timing as 'chronic' phase and analyzed the molecular machinery regulating the chronic response. As a result, we identified CREB as a transcription factor which is activated in this period. CREB induced the expression of Matrix metalloproteinase MMP1, and involved in cancer metastasis. Further, comprehensive analysis of nuclear gene position using High-throughput Imaging Position Mapping (HIPMap) method revealed that conformational changes of chromatin occurs in various gene regions under hypoxic conditions. In this review, molecular machinery of chronic hypoxic response based on our study is discussed.