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lüll hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria Gotoh T; Terada K; Oyadomari S; Mori MCell Death Differ 2004[Apr]; 11 (4): 390-402We reported that the endoplasmic reticulum (ER) stress pathway involving CHOP, a member of the C/EBP transcription factor family, plays a key role in nitric oxide (NO)-mediated apoptosis of macrophages and pancreatic beta cells. We also showed that the cytosolic chaperone pair of hsp70 and dj1 (hsp40/hdj-1) or dj2 (HSDJ/hdj-2) prevents NO-mediated apoptosis upstream of cytochrome c release from mitochondria. To analyze roles of the chaperone pair in preventing apoptosis, RAW 264.7 macrophages stably expressing hsp70 and dj1 or dj2 were established. The chaperone pair prevented LPS/IFN-gamma-induced and NO-mediated apoptosis downstream of CHOP induction. hsp70 mutant protein lacking the ATPase domain or the C-terminal EEVD sequence were not effective in preventing CHOP-induced apoptosis. A mutant dj2 lacking the C-terminal prenylation CaaX motif, was also not effective. When wild-type RAW 264.7 cells were treated with LPS/IFN-gamma, NO-mediated apoptosis was induced, and proapoptotic Bcl-2 family protein Bax was translocated from cytosol to mitochondria. This translocation was prevented in cells stably expressing hsp70/dj2, and in CHOP knockout cells. Overexpression of CHOP in wild-type cells also induced translocation of Bax and this translocation was prevented in cells expressing hsp70/dj2. CHOP-induced apoptosis was prevented by Bax knock-down. Coimmunoprecipitation experiments showed that Bax interacts with both hsp70 and dj1/dj2. ATPase domain of hsp70 was necessary for the binding with Bax. These findings indicate that CHOP-induced apoptosis is mediated by translocation of Bax from the cytosol to the mitochondria, and hsp70/dj1 or dj2 chaperone pair prevents apoptosis by interacting with Bax and preventing translocation to the mitochondria.|*Proto-Oncogene Proteins c-bcl-2[MESH]|Adenosine Triphosphatases/metabolism[MESH]|Animals[MESH]|Apoptosis/physiology[MESH]|CCAAT-Enhancer-Binding Proteins/*antagonists & inhibitors/metabolism[MESH]|COS Cells[MESH]|Cell Line[MESH]|Chlorocebus aethiops[MESH]|Cytosol/metabolism[MESH]|HSP40 Heat-Shock Proteins[MESH]|HSP70 Heat-Shock Proteins/genetics/*physiology[MESH]|Heat-Shock Proteins/genetics/*physiology[MESH]|Macrophages/cytology/metabolism[MESH]|Mice[MESH]|Mice, Knockout[MESH]|Mitochondria/metabolism[MESH]|Molecular Chaperones/metabolism/*pharmacology[MESH]|Nitric Oxide/*antagonists & inhibitors[MESH]|Protein Transport/physiology[MESH]|Proto-Oncogene Proteins/antagonists & inhibitors/*metabolism[MESH]|Transcription Factor CHOP[MESH]|Transcription Factors/*antagonists & inhibitors/metabolism[MESH]|Transfection[MESH]|bcl-2-Associated X Protein[MESH] |