RRC ID 1375
Author Watanabe M, Kitano T, Kondo T, Yabu T, Taguchi Y, Tashima M, Umehara H, Domae N, Uchiyama T, Okazaki T.
Title Increase of nuclear ceramide through caspase-3-dependent regulation of the "sphingomyelin cycle" in Fas-induced apoptosis.
Journal Cancer Res.
Abstract Regardless of the existence of ceramide-related molecules, such as sphingomyelin (SM), neutral sphingomyelinase (nSMase), and SM synthase, in the nucleus, the regulation of ceramide in the nucleus is poorly understood in stress-induced apoptosis. In Fas-induced Jurkat T-cell apoptosis, we found a time- and dose-dependent increase of ceramide content in the nuclear and microsomal fractions. Fas-induced increase of ceramide content in the nucleus also was detected by confocal microscopy using anticeramide antibody. Activation of nSMase and inhibition of SM synthase were evident in the nuclear fraction after Fas cross-linking, whereas nSMase was activated, but SM synthase was not affected, in the microsomal fraction. Pretreatment with D-609, a putative SM synthase inhibitor, enhanced Fas-induced increase of ceramide in the nucleus and induction of apoptosis along with increase of Fas-induced inhibition of nuclear SM synthase. Fas-induced activation of caspase-3 was detected in the nuclear fraction and in whole cell lysate. A caspase-3 inhibitor, acetyl-Asp-Glu-Val-Asp-chloromethyl ketone, blocked not only Fas-induced increases of apoptosis and ceramide content but also Fas-induced activation of nSMase and inhibition of SM synthase in the nuclear fraction. Taken together, it is suggested that the nucleus is a site for ceramide increase and caspase-3 activation in Fas-induced Jurkat T-cell apoptosis and that caspase-3-dependent regulation of the "SM cycle" consisting of nSMase and SM synthase plays a role in Fas-induced ceramide increase in the nucleus.
Volume 64(3)
Pages 1000-7
Published 2004-2-1
PMID 14871831
MeSH Amino Acid Chloromethyl Ketones / pharmacology Apoptosis / physiology* Bridged-Ring Compounds / pharmacology Caspase 3 Caspase Inhibitors Caspases / metabolism* Cell Nucleus / metabolism Ceramides / biosynthesis* Cysteine Proteinase Inhibitors / pharmacology Enzyme Activation Humans Jurkat Cells Phosphodiesterase Inhibitors / pharmacology Sphingomyelin Phosphodiesterase / antagonists & inhibitors Sphingomyelin Phosphodiesterase / metabolism Sphingomyelins / metabolism* T-Lymphocytes / cytology T-Lymphocytes / enzymology T-Lymphocytes / metabolism Thiones / pharmacology Transferases (Other Substituted Phosphate Groups) / antagonists & inhibitors Transferases (Other Substituted Phosphate Groups) / metabolism fas Receptor / physiology*
IF 8.378
Times Cited 48
Human and Animal Cells Jurkat