APOPTOSIS SIGNAL-REGULATING KINASE 1: AS A NOVEL REGULATOR OF THE GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE STRESS-SIGNALING CASCADE

ASK1;GAPDH;Siah1;cell death;oxidative stress;Neuroscience

Tristan, Carlos AlbertoSawa, Akira ;

Johns Hopkins University

关键词: ASK1;    GAPDH;    Siah1;    cell death;    oxidative stress;    Neuroscience;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39278/TRISTAN-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

GAPDH is a classical glycolytic enzyme that has recently been demonstrated to play critical roles outside of glycolysis.These multifunctional roles include the ability for GAPDH to function in DNA repair, membrane fusion, cytoskeletal dynamics, and cell death.These acquired multifunctional roles of are largely dictated by its subcellular localization or by posttranslocation modifications that push GAPDH from the cytoplasm to various subcellular niches.Among several posttranslational modifications, oxidation of GAPDH at C150 is one of the most well characterized modifications that have established GAPDH as a sensor of oxidative stress. In the presence of oxidative stress, oxidation of GAPDH mediates its translocation to the nucleus, via Siah1, where it mediates a stress response, cell death or cellular dysfunction in a ;;gain-of-toxic function” manner.Recently, an increasing number of studies have demonstrated that nuclear translocation of GAPDH plays an underlying role in the manifestation of disease, such as in, cancer, cardiovascular disease, neurodegeneration, ischemia and major mental illness.Although the oxi-GAPDH stress-signaling cascade is well characterized, whether other molecules can regulate this signaling cascade remains poorly understood.This thesis will focus on the GAPDH-Siah1 stress-signaling cascade and identifies a novel regulator.Chapter I provides an overview of the multifunctional roles of GAPDH within distinct subcellular domains, its medical implications and future perspectives.Chapter II identifies both ASK1 as regulator of the GAPDH-Siah1 stress-signaling cascade and Siah1 as a novel substrate of ASK1.We show that phosphorylation of Siah1 by ASK1 induces nuclear translocation of GAPDH and p300 acetylation.In Chapter III, we conclude that ASK1 and Siah1 might be potential therapeutic targets to regulate the GAPDH-Siah1 stress-signaling cascade in disease.