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

The alkylating agent temozolomide, in combination with surgery and radiation, is the current standard of care for patients with glioblastoma. However, despite this extensive therapeutic effort, the inclusion of temozolomide extends survival only by a few short months. Among the factors contributing to chemoresistance is elevated expression of the endoplasmic reticulum (ER) chaperone GRP78 (glucose-regulated protein 78; BiP), a key pro-survival component of the ER stress response system. Because the green tea component EGCG (epigallocatechin 3-gallate) had been shown to inhibit GRP78 function, we investigated whether this polyphenolic agent would be able to increase the therapeutic efficacy of temozolomide in preclinical models of glioblastoma. Mice with intracranially implanted human U87 (p53 wild type) or U251 (p53 mutant) glioblastoma cells were treated with temozolomide and EGCG, alone and in combination. We found that EGCG alone did not provide survival benefit, but significantly improved the existing therapeutic effect of temozolomide, i.e., life extension was substantially greater under combination therapy as compared to temozolomide therapy alone. Immunohistochemical analysis of tumor tissue revealed increased expression levels of GRP78 in temozolomide-treated animals, which was diminished when temozolomide was combined with EGCG. Parallel in vitro experiments with siRNA targeting GRP78 or its major pro-apoptotic antagonist CHOP (CCAAT/enhancer binding protein homologous protein/GADD153) further established a critical role of the ER stress response system, where si-GRP78 sensitized cells to treatment with temozolomide, and si-CHOP provided protection from drug-induced toxicity. Thus, ER stress-regulatory components affect the chemotherapeutic response of glioblastoma cells to treatment with temozolomide, and inclusion of EGCG is able to increase the therapeutic efficacy of this DNA-damaging agent.
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PMID:Green tea epigallocatechin gallate enhances therapeutic efficacy of temozolomide in orthotopic mouse glioblastoma models. 2125 59

The macrophage MR has been the subject of investigation for over 20 years, and several important physiological functions have been described. However, the molecular mechanisms that regulate MR signaling and trafficking during these processes still remain elusive. The focus of the current paper was to identify potential cellular MR-interacting proteins. An initial screen of binding proteins in MR-expressing cells was performed using coimmunoprecipitation, followed by identification of matching peptide sequences using proteomics and MS. The major class of binding proteins identified belonged to the heat shock family of proteins. The specific interaction of the MR with HSP70 family members was validated by Western blot analysis, ligand binding assays, and intracellular colocalization using confocal microscopy. Additional studies indicated that inhibition of the HSP BiP by treatment of cells with EGCG reduced BiP interaction with and surface expression of the MR. Studies of possible motifs within the cytoplasmic tail of the receptor suggested that a juxtamembrane dibasic sequence may contribute to the interaction with BiP. These findings suggest that the molecular association of the MR with HSP70 family members via the receptor cytoplasmic tail may contribute to MR trafficking in macrophages.
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PMID:Interaction of members of the heat shock protein-70 family with the macrophage mannose receptor. 2334 93

In this study the mechanism of avian reovirus (ARV) S1133-induced pathogenesis was investigated, with a focus on the contribution of ER stress to apoptosis. Our results showed that upregulation of the ER stress response protein, as well as caspase-3 activation, occurred in ARV S1133-infected cultured cells and in SPF White Leghorn chicks organs. Upon infection, Bim was translocated specifically to the ER, but not mitochondria, in the middle to late infectious stages. In addition, ARV S1133 induced JNK phosphorylation and promoted JNK-Bim complex formation, which correlated with the Bim translocation and apoptosis induction that was observed at the same time point. Knockdown of BiP/GRP78 by siRNA and inhibition of BiP/GRP78 using EGCG both abolished the formation of the JNK-Bim complex, caspase-3 activation, and subsequent apoptosis induction by ARV S1133 efficiently. These results suggest that BiP/GRP78 played critical roles and works upstream of JNK-Bim in response to the ARV S1133-mediated apoptosis process.
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PMID:Avian reovirus S1133-induced apoptosis is associated with Bip/GRP79-mediated Bim translocation to the endoplasmic reticulum. 2557 94