理学院学术报告-Oxygen threshold-dependent activation of hydroxylase determines HIF-1α-coordinated cellular adaptation to hypoxia

报告题目：Oxygen threshold-dependent activation of hydroxylase determines HIF-1α-coordinated cellular adaptation to hypoxia

报 告 人：王平

报告时间：2023年6月8日 10:00

报告地点：6D-414

主办单位：理学院

主讲人简介：

    Wang Ping received a bachelor's degree in physics from Capital Normal University in 2011; a master's degree in physics from North China Electric Power University in 2014; and a Ph.D. in physics from Nanjing University in 2019. From October 2019 to June 2022, she was engaged in postdoctoral research at Kuang Yaming College, Nanjing University. She is currently a lecturer at the School of Science, Xihua University, Chengdu. Her current research interests are theoretical biophysics/computational systems biology, especially the dynamics of cancer-related cellular signaling networks.

内容简介：

    HIF-1 plays a cruical role in adaptation of tumor cells to environmental hypoxia. By inducing the expression of tar-get genes, HIF-1 mediates multiple cellular processes, including glycolysis activation, tumor vascularization, and inflammation-associated necrosis. The rationale for which cellular processes HIF-1 triggers in response to graded hypoxia remains unclear.Here, we developed an integrated HIF-1 network model, which comprsies the upstream regulaory circuits and downstream effector-regulated selection of cellular outcomes. We found that the selectivity of target genes depends on the transcriptional activity of HIF-1, which is subjected to the coupled HIF-1 /PHD-2/FIH/miR-182 feedback loops. As a result, glycolysis, angio-genesis, and necrosis are sequentially activated with increasing the severity of hypoxia. Unlike the inactivation of FIH caused by the lack of oxygen molecules under severe hypoxia, moderate hypoxia-induced miR-182 can reduce FIH expression, allowing the initial accumulation of fully activated HIF-1 for VEGF induction and selection of target genes. Glycolysis is activated in a two-step manner; its initial activation involves inducing glycolytic enzymes (e.g., PFKL) during mild and moderate hypoxia and further activation involves increasing glucose transporters (e.g., GLUT-1) during severe hypoxia. To avoid the accumulation of lactic acid caused by enhanced glycolysis, HIF-1 activates MCT and CA9 sequentially/step-by-step to export intracellular hy-drogen ions, thus creating an internal alkaline and external acid cellular environment suitable for tumor growth. The imbalance of accumulation and removal of lactic acid in severe hypoxia leads to acidosis and further induces cell necrosis.