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 NaAsO2-induced signal cascades from the cell surface to the nucleus of murine thymic T lymphocytes that involve membrane rafts as an initial signal transducer. NaAsO2 induced apoptosis through fragmenta tion of DNA, activation of caspase, and reciprocal regulation of Bcl-2/Bax with the concomitant reduction of membrane potential. We demonstrated that NaAsO2-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 NaAsO2-media ted signal for poly(ADP-ribose) polymerase (PARP) degradation Potentially a s the initial cell, surface event for intracellular signaling, NaAsO2 induc ed aggregation of GPI-anchored protein Thy-1 and superoxide production. Thi s Thy-1 aggregation and subsequent activation of MAP family kinase and c-Ju n and the degradation of PARP induced by NaAsO2 were all inhibited by DTT, suggesting the requirement of interaction between arsenic and protein sulfh ydryl groups for those effects. beta cyclodextrin, which sequestrates chole sterol from the membrane rafts, inhibited NaAsO2-induced activation of prot ein tyrosine kinases and MAP family kinases, degradation of PARP, and produ ction of superoxide, In addition, beta cyclodextrin dispersed NaAsO2-induce d Thy-1 clustering, These results suggest that a membrane raft integrity-de pendent cell surface event is a prerequisite for NaAsO2-induced protein tyr osine kinase/c-Jun amino-terminal kinase activation, superoxide production, and downstream caspase activation.