Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response.

@article{citeulike:2459263, abstract = {Cadmium triggers apoptosis of LLC-PK1 cells through induction of endoplasmic reticulum (ER) stress. We found that cadmium caused generation of reactive oxygen species (ROS) and that cadmium-induced ER stress was inhibited by antioxidants. In contrast, suppression of ER stress did not attenuate cadmium-triggered oxidative stress, suggesting that ER stress occurs downstream of oxidative stress. Exposure of the cells to either O(2)(.), H(2)O(2), or ONOO(-) caused apoptosis, whereas ER stress was induced only by O(2)(.) or ONOO(-). Transfection with manganese superoxide dismutase significantly attenuated cadmium-induced ER stress and apoptosis, whereas pharmacological inhibition of ONOO(-) was ineffective. Interestingly, transfection with catalase attenuated cadmium-induced apoptosis without affecting the level of ER stress. O(2)(.) caused activation of the activating transcription factor 6-CCAAT/enhancer-binding protein-homologous protein (CHOP) and the inositol-requiring ER-to-nucleus signal kinase 1-X-box-binding protein 1 (XBP1) proapoptotic cascades, and overexpression of manganese superoxide dismutase attenuated cadmium-triggered induction of both pathways. Furthermore, phosphorylation of proapoptotic c-Jun N-terminal kinase by O(2)(.) or cadmium was suppressed by dominant-negative inhibition of XBP1. These data elucidated 1) cadmium caused ER stress via generation of ROS, 2) O(2)(.) was selectively involved in cadmium-triggered, ER stress-mediated apoptosis through activation of the activating transcription factor 6-CHOP and inositol-requiring ER-to-nucleus signal kinase 1-XBP1 pathways, and 3) phosphorylation of JNK was caused by O(2)(.)-triggered activation of XBP1.}, address = {Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato 1110, Chuo, Yamanashi 409-3898, Japan.}, author = {Yokouchi, M. and Hiramatsu, N. and Hayakawa, K. and Okamura, M. and Du, S. and Kasai, A. and Takano, Y. and Shitamura, A. and Shimada, T. and Yao, J. and Kitamura, M. }, citeulike-article-id = {2459263}, doi = {10.1074/jbc.M705951200}, issn = {0021-9258}, journal = {J Biol Chem}, month = {February}, number = {7}, pages = {4252--4260}, posted-at = {2008-03-03 04:00:58}, priority = {2}, title = {Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response.}, url = {http://dx.doi.org/10.1074/jbc.M705951200}, volume = {283}, year = {2008} }

TY - JOUR ID - citeulike:2459263 L3 - citeulike-article-id:2459263 TI - Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response. JF - J Biol Chem VL - 283 IS - 7 SP - 4252 EP - 4260 AD - Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato 1110, Chuo, Yamanashi 409-3898, Japan. SN - 0021-9258 N2 - Cadmium triggers apoptosis of LLC-PK1 cells through induction of endoplasmic reticulum (ER) stress. We found that cadmium caused generation of reactive oxygen species (ROS) and that cadmium-induced ER stress was inhibited by antioxidants. In contrast, suppression of ER stress did not attenuate cadmium-triggered oxidative stress, suggesting that ER stress occurs downstream of oxidative stress. Exposure of the cells to either O(2)(.), H(2)O(2), or ONOO(-) caused apoptosis, whereas ER stress was induced only by O(2)(.) or ONOO(-). Transfection with manganese superoxide dismutase significantly attenuated cadmium-induced ER stress and apoptosis, whereas pharmacological inhibition of ONOO(-) was ineffective. Interestingly, transfection with catalase attenuated cadmium-induced apoptosis without affecting the level of ER stress. O(2)(.) caused activation of the activating transcription factor 6-CCAAT/enhancer-binding protein-homologous protein (CHOP) and the inositol-requiring ER-to-nucleus signal kinase 1-X-box-binding protein 1 (XBP1) proapoptotic cascades, and overexpression of manganese superoxide dismutase attenuated cadmium-triggered induction of both pathways. Furthermore, phosphorylation of proapoptotic c-Jun N-terminal kinase by O(2)(.) or cadmium was suppressed by dominant-negative inhibition of XBP1. These data elucidated 1) cadmium caused ER stress via generation of ROS, 2) O(2)(.) was selectively involved in cadmium-triggered, ER stress-mediated apoptosis through activation of the activating transcription factor 6-CHOP and inositol-requiring ER-to-nucleus signal kinase 1-XBP1 pathways, and 3) phosphorylation of JNK was caused by O(2)(.)-triggered activation of XBP1. AU - Yokouchi, M AU - Hiramatsu, N AU - Hayakawa, K AU - Okamura, M AU - Du, S AU - Kasai, A AU - Takano, Y AU - Shitamura, A AU - Shimada, T AU - Yao, J AU - Kitamura, M PY - 2008/02/15/ UR - http://dx.doi.org/10.1074/jbc.M705951200 ER -