Regulation of ceramide synthase 1 in cellular stress response

Title from PDF of title page (University of Missouri--Columbia, viewed on Feb 25, 2010).The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file.Dissertation advisor: Dr. Stephen Alexander and Dr. Hannah Alexander.Vita.Ph. D. University of Missouri--Columbia 2008.[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Ceramides are intimately involved in a wide range of cellular processes. In mammals, de novo ceramide synthesis is catalyzed by the 6 ceramide synthase enzymes, which are homologs of the yeast longevity assurance gene (lag). CerS1 catalyzes the synthesis of C18-ceramide, which has important roles in cell signaling, inflammation and apoptosis. In this study we show that CerS1 is a short-lived protein and that it undergoes stress-induced turnover in an ubiquitination and proteasome-dependent manner. This turnover is regulated by protein kinase C (PKC) and the p38 MAP kinase. This study also focuses on the stress-induced endoplasmic reticulum (ER) to Golgi translocation of the CerS1 protein. We show that CerS1 undergoes proteasome-dependent proteolytic cleavage under stress, as a result of which N-terminus CerS1 is degraded, while the Cterminus CerS1 translocates to the Golgi apparatus, also regulated in a PKC-dependent manner. Overall this study describes a novel regulatory mechanism for an important sphingolipid enzyme.Includes bibliographical references