Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory response has recently been shown to induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which either recovers proper ER function or activates apoptosis. Here we show that endotoxin (lipopolysaccharide = LPS) can lead to functional ER failure tentatively via a mitochondrion-dependent pathway in livers of rats. Histological examination did not reveal significant damage to liver in form of necroses. Electron microscopy displayed transparent rings appearing around morphologically unchanged mitochondria, which were identified as dilated ER. The spliced mRNA variant of X-box protein-1 (XBP1) and also the mRNA of 78 kDa glucose-regulated protein (GRP78) were up-regulated, both typical markers of ER stress. However, GRP78 was down-regulated at the protein level. A pro-apoptotic shift in the bax/bcl-XL mRNA ratio was not accompanied by translocation of apoptosis inducing factor (AIF) to the nucleus, suggesting that the cells entered a pre-apoptotic state, but apoptosis was not executed. Monooxygenase activity of p450, representing the detoxification system in ER, was decreased after administration of endotoxin. Biochemical analysis of proteins important for ER function revealed the impairment of protein folding, transport, and detoxification suggesting functional ER failure. We suggest that functional ER failure may be a reason for organ dysfunction upon excessive inflammatory response mediated by endotoxin.
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PMID:Endotoxin causes functional endoplasmic reticulum failure, possibly mediated by mitochondria. 1932 97

Subtilase cytotoxin (SubAB) is an AB(5) cytotoxin produced by some strains of Shiga-toxigenic Escherichia coli. The A subunit is a subtilase-like serine protease and cleaves an endoplasmic reticulum (ER) chaperone, BiP, leading to transient inhibition of protein synthesis and cell cycle arrest at G(1) phase, and inducing caspase-dependent apoptosis via mitochondrial membrane damage in Vero cells. Here we investigated the mechanism of mitochondrial permeabilization in HeLa cells. SubAB-induced cytochrome c release into cytosol did not depend on mitochondrial permeability transition pore (PTP), since cyclosporine A did not suppress cytochrome c release. SubAB did not change the expression of anti-apoptotic Bcl-2 or Bcl-XL and pro-apoptotic Bax or Bak, but triggered Bax and Bak conformational changes and association of Bax with Bak. Silencing using siRNA of both bax and bak genes, but not bax, bak, or bim alone, resulted in reduction of cytochrome c release, caspase-3 activation, DNA ladder formation and cytotoxicity, indicating that Bax and Bak were involved in apoptosis. SubAB activated ER transmembrane transducers, Ire1alpha, and cJun N-terminal kinase (JNK), and induced C/EBF-homologue protein (CHOP). To investigate whether these signals were involved in cytochrome c release by Bax activation, we silenced ire1alpha, jnk or chop; however, silencing did not decrease SubAB-induced cytochrome c release, suggesting that these signals were not necessary for SubAB-induced mitochondrial permeabilization by Bax activation.
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PMID:Subtilase cytotoxin induces apoptosis in HeLa cells by mitochondrial permeabilization via activation of Bax/Bak, independent of C/EBF-homologue protein (CHOP), Ire1alpha or JNK signaling. 2056 23

Subtilase cytotoxin (SubAB) was first isolated from a Shiga toxigenic Escherichia coli (STEC) strain that was responsible for an outbreak of hemolytic-uremic syndrome and is the prototype of a new family of AB(5) cytotoxins. SubAB is a subtilase-like serine protease, and upon uptake by host cells, it is trafficked to the endoplasmic reticulum (ER), where it cleaves the essential ER chaperone BiP (GRP78) with high specificity. Previous work has shown that BiP cleavage by SubAB initiates ER stress-signaling pathways in host cells that eventuate in cell death associated with DNA fragmentation, a hallmark of apoptosis. The present study has investigated the role of the Bcl-2 protein family, which has been shown to regulate ER stress-induced apoptosis in other model systems. Examination of the cytotoxicity of SubAB for wild-type and bax(-/-)/bak(-/-) mouse embryonic fibroblasts and comparison of apoptotic markers in these cells revealed that SubAB cytotoxicity can be predominantly attributed to the activation of apoptotic pathways activated by Bax/Bak. The results of the present study further our understanding of the molecular mechanism whereby SubAB kills eukaryotic cells and contributes to STEC pathogenesis, in addition to consolidating the roles of Bcl-2 family members in the regulation of ER stress-induced apoptosis.
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PMID:Escherichia coli subtilase cytotoxin induces apoptosis regulated by host Bcl-2 family proteins Bax/Bak. 2071 20