Journal of Biochemistry Advance Access originally published online on May 13, 2008
Journal of Biochemistry 2008 144(2):251-257; doi:10.1093/jb/mvn063
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© 2008 The Japanese Biochemical Society
Nicotine Suppresses Tunicamycin-Induced, But Not Thapsigargin-Induced, Expression of GRP78 during ER Stress-Mediated Apoptosis in PC12 Cells
1Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and High Technology Research Center (HRC), Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680; and 2Department of Pharmacology, Nara Medical University School of Medicine, 840 Shijo-Chou, Kashihara, Nara 634-8521, Japan
*To whom correspondence should be addressed. Tel: +81 6 6368 0920, Fax: +81 6 6330 3770, E-mail: ikeuchi{at}ipcku.kansai-u.ac.jp
Received March 19, 2008; Accepted May 2, 2008
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Abstract |
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We previously reported that nicotine protected against tunicamycin (Tm)-induced ER stress-mediated apoptosis, but not thapsigargin (Tg)-induced apoptosis in PC12 cells. In the present study, we report that the expression of glucose-regulated protein 78 (GRP78) was suppressed by nicotine in Tm-treated PC12 cells. Interestingly, the GRP78 expression was not changed by nicotine in Tg-treated cells. Moreover, nicotine reduced the activation of caspase-12 in Tm-treated cells, but not in Tg-treated cells. These results suggest that nicotine prevented Tm-induced ER stress-mediated apoptosis by attenuating an early stage of Tm-induced ER stress. It was possible that the suppression of GRP78 expression by nicotine was achieved through the suppression of the Ire1-XBP1 and/or ATF6 pathways. We observed that nicotine suppressed the Tm-induced, but not Tg-induced, splicing of XBP1 mRNA, and also suppressed the Tm-induced, but not Tg-induced, production of cleaved ATF6 in PC12 cells. These results indicate that the suppression of Ire1-XBP1 and ATF6 pathways contributes to the suppression of GRP78 expression by nicotine in Tm-treated PC12 cells, suggesting that nicotine suppresses a common step upstream of both the Ire1-XBP1 and ATF6 pathways which are required for the expression of GRP78 during Tm-induced ER stress.
Key Words: apoptosis, ER stress, glucose-regulated protein 78, nicotine, PC12 cell
Abbreviations: ATF6, activating transcription factor 6; ER, endoplasmic reticulum; ERSE, ER stress response element; GRP78, glucose regulated protein 78; IRE1, inositol-requiring transmembrane kinase and endonuclease 1; JNK, c-Jun N-terminal kinase; Nup153, nucleoporin 153; PERK, PKR-like ER kinase; S1P, site 1 protease; S2P, site 2 protease; UPR, unfolded protein response; XBP1, X box-binding protein 1