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MBC in Press, published online ahead of print January 12, 2005
Mol. Biol. Cell 10.1091/mbc.E04-07-0594

A more recent version of this article appeared on March 1, 2005
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Submitted on July 15, 2004
Revised on November 22, 2004
Accepted on December 7, 2004

Golgi Fragmentation Is Associated with Ceramide-induced Cellular Effects

Wei Hu,*{dagger} Ruijuan Xu,* Guofeng Zhang,{ddagger} Junfei Jin,* Zdzislaw M. Szulc,{dagger} Jacek Bielawski,{dagger} Yusuf A. Hannun,{dagger} Lina M. Obeid,*{dagger}{sect} and Cungui Mao*{dagger}||

*Departments of Medicine and Biochemistry and {dagger}Molecular Biology, Medical University of South Carolina, Charleston, SC 29425; {ddagger}Division of Bioengineering and Physical Sciences, National Institutes of Health, Bethesda, MD 20892; and {sect}Ralph H. Johnson Veterans Administration Hospital, Charleston, SC 29401-5799

Monitoring Editor: Vivek Malhotra

Ceramide has been shown to cause anoikis, a subtype of apoptosis due to inadequate cell adhesion. However, the underlying mechanism is unclear. Herein we report that D-e-C6-ceramide (D-e-Cer), via generating sphingosine, disrupts the Golgi complex (GC), which is associated with various cellular effects including anoikis. Treatment of HeLa cells with D-e-Cer caused cell elongation, spreading inhibition, rounding, and detachment before apoptosis (anoikis). In D-e-Cer-treated cells, glycosylation of {beta}1 integrin in the GC was inhibited, thus its associated integrin receptors failed to translocate to the cell surface. Ceramide treatment also inhibited the reorganization of both microtubule and F-actin cytoskeletons, focal adhesions, and filopodia. These cellular effects were preceded by fragmentation of the Golgi complex. In contrast, L-e-C6-ceramide (L-e-Cer), the enantiomer of D-e-Cer, failed to induce these cellular effects. Mass spectrometric analysis revealed that treatment HeLa cells with D-e-Cer but not L-e-Cer caused a more than 50-fold increase in the levels of sphingosine, a product of hydrolysis of ceramide. Treatment with D-e-sphingosine and its enantiomer, L-e-sphingosine, caused massive perinuclear vacuolization, Golgi fragmentation, and cell rounding. Taken together, these results suggest that sphingosine generated from hydrolysis of ceramide causes the GC disruption, leading to various cellular effects.

||Corresponding author. E-mail: maoc{at}musc.edu






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