Suppression of ceramide-mediated apoptosis by HSP70.
Ceramide has been known as an important second messenger in programmed cell death (apoptosis) which is induced by various stimuli such as the tumor necrosis factor-alpha (TNF-alpha), Fas ligand, and environmental stresses such as UV-irradiation and heat shock. Although the precise molecular mechanism of apoptosis is not fully understood, ceramide generated by sphingomyelinase (SMase) mediates the activation of several downstream molecules that are implicated in the regulation of apoptosis. Here, we show that stress-inducible heat shock protein 70 (Hsp70) prevents apoptosis induced by increased level of intracellular ceramide. In T-cell hybridoma DO11.10, we examined the effect of Hsp70 on apoptosis mediated by TNF-alpha, Fas ligation, SMase, and C2-ceramide, all of which elevate intracellular ceramide levels. Hsp70 not only markedly reduced internucleosomal DNA fragmentation, but also enhanced cell viability measured by the Trypan blue dye exclusion test. Similarly, the ceramide-induced c-jun amino-terminal kinase (JNK/SAPK) activation is impaired in cells overexpressing Hsp70. These data strongly suggest that hsp70 functions as a regulator of apoptosis downstream of ceramide.
Ahn
J H
JH
ILCHUN Institute for Molecular Medicine and Department of Biochemistry, Seoul National University College of Medicine, Korea.
Ko
Y G
YG
Park
W Y
WY
Kang
Y S
YS
Chung
H Y
HY
Seo
J S
JS
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D002518:Ceramides / Q000502:physiology*; D053938:DNA Fragmentation; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006825:Hybridomas; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology
D002518:Ceramides; D018840:HSP70 Heat-Shock Proteins; D011993:Recombinant Fusion Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases