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Published on: April 18, 2016
Ceramide synthase 1 is regulated by proteasomal mediated turnover
Priya Sridevi1, Hannah Alexander, Elad L Laviad
1Division of Biological Sciences, University of Missouri, Columbia, MO 65211, USA.
Biochimica Et Biophysica Acta
|April 28, 2009
Summary
This study reveals how ceramide synthase 1 (CerS1) levels are regulated by protein turnover. Stress and signaling pathways control CerS1 stability, impacting ceramide homeostasis.
Area of Science:
- Biochemistry
- Cell Biology
- Lipid Metabolism
Background:
- Ceramides are vital bioactive lipids regulating cell death, cancer, and chemotherapy.
- Six ceramide synthases (CerS) synthesize ceramides, each with distinct substrate preferences and tissue distribution.
- Regulation of CerS enzymes, particularly CerS1, remains poorly understood.
Purpose of the Study:
- To elucidate the regulatory mechanism controlling ceramide synthase 1 (CerS1) protein levels.
- To investigate the role of ubiquitination and proteasome-dependent turnover in CerS1 regulation.
- To identify signaling pathways influencing CerS1 stability.
Main Methods:
- Investigated CerS1 turnover using endogenous and ectopically expressed proteins.
- Applied various cellular stresses including chemotherapeutic drugs, UV light, and DTT.
- Utilized biochemical assays to assess CerS1 activity, phosphorylation, and interactions with kinases.
- Examined the roles of p38 MAP kinase and protein kinase C (PKC) in CerS1 regulation.
Main Results:
- CerS1 exhibits rapid basal turnover, which is enhanced by cellular stresses.
- CerS1 turnover is dependent on its enzymatic activity.
- p38 MAP kinase promotes CerS1 turnover, while PKC inhibits it.
- PKC activation increases CerS1 phosphorylation, suggesting a role in regulating turnover.
Conclusions:
- A novel ubiquitination-dependent mechanism regulates CerS1 protein levels.
- CerS1 stability is dynamically controlled by opposing kinase pathways (p38 MAP kinase and PKC).
- This regulation of CerS1 directly impacts ceramide homeostasis and cellular responses to stress.
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