Date of Award

2003

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

Julio Barredo

Second Advisor

Yusuf Hannun

Third Advisor

Inderjit Singh

Fourth Advisor

Yi-Te Hsu

Abstract

Ceramide is a sphingolipid second messenger that is involved in apoptosis and other cellular responses to stress. Ceramide generation occurs primarily by two methods: hydrolysis of sphingomyelin by sphingomyelinases or by de novo synthesis, which is initiated on the surface of the endoplasmic reticulum by serine palmitoyltransferase (SPT). The de novo synthesis of ceramide is activated in response to' retinoic acid, chemotherapeutic agents like etoposide or daunorubicin, and TNF-_ . We have shown previously that SPT is activated in response to chemotherapy and governs de novo ceramide production. To determine factors that regulate SPT and the de novo pathway we have investigated this pathway in cells over-expressing Bcl-2. Bcl-2 is a 26-kDa integral membrane oncoprotein that is capable of suppressing apoptosis. It prevents many of the morphological and biochemical changes observed in apoptosis. It was shown that Bcl-2 interrupts apoptosis by different mechanisms such as forming heterodimers with Bax, affecting Ca+2 flux, or preventing the release from the mitochondria of apoptotic activators like cytochrome c and AIF. We herein demonstrate a caspase-dependent induction of de novo ceramide in etoposide-induced apoptosis and its inhibition by Bcl-2.

Rights

All rights reserved. Copyright is held by the author.

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