Arsenite induces apoptosis of murine T lymphocytes through membrane raft-linked signaling for activation of c-Jun amino-terminal kinase.
Because of its dual roles in acute toxicity and in therapeutic application in cancer treatment, arsenic has recently attracted a renewed attention. In this study, we report NaAsO(2)-induced signal cascades from the cell surface to the nucleus of murine thymic T lymphocytes that involve membrane rafts as an initial signal transducer. NaAsO(2) induced apoptosis through fragmentation of DNA, activation of caspase, and reciprocal regulation of Bcl-2/Bax with the concomitant reduction of membrane potential. We demonstrated that NaAsO(2)-induced caspase activation is dependent on curcumin-sensitive c-Jun amino-terminal kinase and barely dependent on SB203580-sensitive p38 kinase or PD98059-sensitive extracellular signal-regulated kinase. Additionally, staurosporine, which severely inhibited the activation of mitogen-activated protein (MAP) family kinases and c-Jun, partially blocked the NaAsO(2)-mediated signal for poly(ADP-ribose) polymerase (PARP) degradation. Potentially as the initial cell surface event for intracellular signaling, NaAsO(2) induced aggregation of GPI-anchored protein Thy-1 and superoxide production. This Thy-1 aggregation and subsequent activation of MAP family kinase and c-Jun and the degradation of PARP induced by NaAsO(2) were all inhibited by DTT, suggesting the requirement of interaction between arsenic and protein sulfhydryl groups for those effects. beta cyclodextrin, which sequestrates cholesterol from the membrane rafts, inhibited NaAsO(2)-induced activation of protein tyrosine kinases and MAP family kinases, degradation of PARP, and production of superoxide. In addition, beta cyclodextrin dispersed NaAsO(2)-induced Thy-1 clustering. These results suggest that a membrane raft integrity-dependent cell surface event is a prerequisite for NaAsO(2)-induced protein tyrosine kinase/c-Jun amino-terminal kinase activation, superoxide production, and downstream caspase activation.
Hossain
K
K
Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Akhand
A A
AA
Kato
M
M
Du
J
J
Takeda
K
K
Wu
J
J
Takeuchi
K
K
Liu
W
W
Suzuki
H
H
Nakashima
I
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D018053:Arsenites / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D007424:Intracellular Fluid / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000276:immunology; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017670:Sodium Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D018053:Arsenites; D010750:Phosphoproteins; D017670:Sodium Compounds; D013481:Superoxides; D014443:Tyrosine; C017947:sodium arsenite; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases