Signal Transduction and Gene Regulation During Hypoxic Stress: A potential Role in Neurodegenerative Disease

摘要

The primary objective of this research project is to determine the role of the mitogen-activated protein kinase (MAPK) pathways (specifically p38 kinase) in mediating the cellular response to hypoxia-stress. The overall scope of this project is to understand how neurons adapt to chronic hypoxia. The neural-like PCl2 cell line is used as a model system to identify the molecular mechanisms that mediate tolerance to hypoxia. The inability to develop tolerance can lead to neurodegeneration and possibly cell death. Our work on this project resulted in the publication of 4 original papers, 1 review paper, and 1 book chapter. We found that exposure to prolonged hypoxia activates the p38 alpha and p38 gamma isoforms, but not the p38 beta% or p38 delta isoforms of the p38 kinase pathway. We showed that the down-stream targets of these p38 kinase isoforms are cyclin Dl and a cyclin A-like molecule. We propose that activation of these cyclins during hypoxia stimulates cell proliferation and might protect neurons in the intact nervous system against damaging effects of hypoxia. We also discovered that the activation of the hypoxia-induced transcription factor, EPAS1, is regulated by the p42/p44 MAPK pathway, but in a manner that is independent of ras but dependent on calcium/calmodulin.