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GRP78 and Raf-1 cooperatively confer resistance to endoplasmic reticulum stress-induced apoptosis.
J Cell Physiol. 2008 Jun; 215(3):627-35.JC

Abstract

The chaperone glucose-regulated protein, 78/immunoglobulin binding protein (GRP78/Bip), protects cells from cytotoxicity induced by DNA damage or endoplasmic reticulum (ER) stress. In this study, we showed that GRP78 is a major inducible protein in human non-small cell lung cancer H460 cells treated with ER stress inducers, including A23187 and thapsigargin. AEBSF, an inhibitor of serine protease, diminished GRP78 induction, enhanced mitochondrial permeability, and augmented apoptosis in H460 cells during ER stress. Simultaneously, AEBSF promoted Raf-1 degradation and suppressed phosphorylation of Raf-1 at Ser338 and/or Tyr340 during ER stress. Coimmunoprecipitation assays and subcellular fractionations showed that GRP78 associated and colocalized with Raf-1 on the outer membrane of mitochondria, respectively. While treatment of cells with ER stress inducers inactivated BAD by phosphorylation at Ser75, a Raf-1 phosphorylation site; AEBSF attenuated phosphorylation of BAD, leading to cytochrome c release from mitochondria. Additionally, overexpression of GRP78 and/or Raf-1 protected cells from ER stress-induced apoptosis. Taken together, our results indicate that GRP78 may stabilize Raf-1 to maintain mitochondrial permeability and thus protect cells from ER stress-induced apoptosis.

Authors+Show Affiliations

Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18064632

Citation

Shu, Chih-Wen, et al. "GRP78 and Raf-1 Cooperatively Confer Resistance to Endoplasmic Reticulum Stress-induced Apoptosis." Journal of Cellular Physiology, vol. 215, no. 3, 2008, pp. 627-35.
Shu CW, Sun FC, Cho JH, et al. GRP78 and Raf-1 cooperatively confer resistance to endoplasmic reticulum stress-induced apoptosis. J Cell Physiol. 2008;215(3):627-35.
Shu, C. W., Sun, F. C., Cho, J. H., Lin, C. C., Liu, P. F., Chen, P. Y., Chang, M. D., Fu, H. W., & Lai, Y. K. (2008). GRP78 and Raf-1 cooperatively confer resistance to endoplasmic reticulum stress-induced apoptosis. Journal of Cellular Physiology, 215(3), 627-35.
Shu CW, et al. GRP78 and Raf-1 Cooperatively Confer Resistance to Endoplasmic Reticulum Stress-induced Apoptosis. J Cell Physiol. 2008;215(3):627-35. PubMed PMID: 18064632.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GRP78 and Raf-1 cooperatively confer resistance to endoplasmic reticulum stress-induced apoptosis. AU - Shu,Chih-Wen, AU - Sun,Fang-Chun, AU - Cho,Jun-Hung, AU - Lin,Chih-Chien, AU - Liu,Pei-Feng, AU - Chen,Ping-Yen, AU - Chang,Margaret Dah-Tsyr, AU - Fu,Hua-Wen, AU - Lai,Yiu-Kay, PY - 2007/12/8/pubmed PY - 2008/4/30/medline PY - 2007/12/8/entrez SP - 627 EP - 35 JF - Journal of cellular physiology JO - J Cell Physiol VL - 215 IS - 3 N2 - The chaperone glucose-regulated protein, 78/immunoglobulin binding protein (GRP78/Bip), protects cells from cytotoxicity induced by DNA damage or endoplasmic reticulum (ER) stress. In this study, we showed that GRP78 is a major inducible protein in human non-small cell lung cancer H460 cells treated with ER stress inducers, including A23187 and thapsigargin. AEBSF, an inhibitor of serine protease, diminished GRP78 induction, enhanced mitochondrial permeability, and augmented apoptosis in H460 cells during ER stress. Simultaneously, AEBSF promoted Raf-1 degradation and suppressed phosphorylation of Raf-1 at Ser338 and/or Tyr340 during ER stress. Coimmunoprecipitation assays and subcellular fractionations showed that GRP78 associated and colocalized with Raf-1 on the outer membrane of mitochondria, respectively. While treatment of cells with ER stress inducers inactivated BAD by phosphorylation at Ser75, a Raf-1 phosphorylation site; AEBSF attenuated phosphorylation of BAD, leading to cytochrome c release from mitochondria. Additionally, overexpression of GRP78 and/or Raf-1 protected cells from ER stress-induced apoptosis. Taken together, our results indicate that GRP78 may stabilize Raf-1 to maintain mitochondrial permeability and thus protect cells from ER stress-induced apoptosis. SN - 1097-4652 UR - https://www.unboundmedicine.com/medline/citation/18064632/GRP78_and_Raf_1_cooperatively_confer_resistance_to_endoplasmic_reticulum_stress_induced_apoptosis_ L2 - https://doi.org/10.1002/jcp.21340 DB - PRIME DP - Unbound Medicine ER -