Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Caspase-8 is believed to play an obligatory role in apoptosis initiation by death receptors, but the role of its structural relative, caspase-10, remains controversial. Although earlier evidence implicated caspase-10 in apoptosis signaling by CD95L and Apo2L/TRAIL, recent studies indicated that these death receptor ligands recruit caspase-8 but not caspase-10 to their death-inducing signaling complex (DISC) even in presence of abundant caspase-10. We characterized a series of caspase-10-specific antibodies and found that certain commercially available antibodies cross-react with HSP60, shedding new light on previous results. The majority of 55 lung and breast carcinoma cell lines expressed mRNA for both caspase-8 and -10; however, immunoblot analysis revealed that caspase-10 protein expression was more frequently absent than that of caspase-8, suggesting a possible selective pressure against caspase-10 production in cancer cells. In nontransfected cells expressing both caspases, CD95L and Apo2L/TRAIL recruited endogenous caspase-10 as well as caspase-8 to their DISC, where both enzymes were proteolytically processed with similar kinetics. Caspase-10 recruitment required the adaptor FADD/Mort1, and caspase-10 cleavage in vitro required DISC assembly, consistent with the processing of an apoptosis initiator. Cells expressing only one of the caspases underwent ligand-induced apoptosis, indicating that each caspase can initiate apoptosis independently of the other. Thus, apoptosis signaling by death receptors involves not only caspase-8 but also caspase-10, and both caspases may have equally important roles in apoptosis initiation.
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PMID:Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8. 1158 96

Postmenopausal osteoporosis is a heterogeneous disorder characterized by accelerated bone loss after natural or surgical menopause and an increased risk of fractures. The bone loss in estrogen deficiency results from the increased bone resorption and impaired ability of osteoblastic bone formation. Previous studies have reported that the HSP60 stimulates osteoclast formation and bone resorption. Here we found that plasma HSP60 levels were significantly higher in postmenopausal (median 1152.4 ng/ml; range 724.7-2123.4 ng/ml) than in premenopausal (median 316.3 ng/ml; range 164.6-638.4 ng/ml) women. In primary human bone marrow stromal cells (hBMSC) and the HS-5 hBMSC cell line, HSP60 significantly reduced cell viability and increased caspase-dependent apoptosis. Consistent with these observations, HSP60 activated caspase-3 and -9, but not caspase-8 in HS-5 cells, and increased the release of mitochondrial cytochrome c into the cytosol. In addition, HSP60 activated p38 and NFkappaB, but not ERK or JNK; importantly, inhibitors of p38 (SB203580) and NFkappaB (PDTC) abolished HSP60-induced apoptosis. Furthermore, Western blotting showed that HSP60 up-regulated TLR-2 and TLR-4 expression, and pretreatment with blocking antibodies for TLR-2 and TLR-4 almost completely eliminated the effects of HSP60 on apoptosis, caspase-3 and -9 activation, and activation of NFkappaB and p38 MAPK. Most notably, ovariectomy-induced bone loss was attenuated in TLR-2 KO mice. In conclusion, up-regulation of TLR-2 by HSP60 may play a critical role in promoting bone loss in the estrogen-deficient state.
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PMID:Increased circulating heat shock protein 60 induced by menopause, stimulates apoptosis of osteoblast-lineage cells via up-regulation of toll-like receptors. 1930 54

Identification of differential proteomic responses to cadmium (Cd) would provide a means for better understanding the survival mechanisms of the earthworm, Eisenia fetida, living in a Cd-polluted environment, and the stress responses can be assessed by ecotoxiptoromics approaches. Extracts of whole earthworm collected at days 7, 14, 21, and 28 after Cd exposure were analyzed by 2-DE and quantitative image analysis. In total, 143 proteins demonstrated significant regulation in at least at one time point, and 56 proteins were identified by MALDI-TOF/TOF-MS and database searching. Compared with control samples, 28 protein spots were up-regulated and 28 were down-regulated during at least one time point. The identified proteins, including chaperonine protein HSP60, caspase-8, calcium ion-binding protein, zinc ion-binding protein, actin-binding protein, proteolysis, fibrinolytic protease, glutamate dehydrogenase, gelsolin-like protein, lombricine kinase, coelomic cytolytic factor 1, manganous superoxide dismutase, extracellular globin-4, lysenin, intermediate filament protein, and tubulin, are involved in several processes, including transcription, translation, the tricarboxylic acid cycle, the cellular amino acid metabolic process, protein amino acid phosphorylation, glycolysis, and the glucose metabolic process. Thus, our study provides a functional profile of the Cd-responsive proteins in earthworms.
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PMID:Analysis of earthworm Eisenia fetida proteomes during cadmium exposure: An ecotoxicoproteomics approach. 2113

Innate immune response after transient ischemia is the most common cause of myocardial inflammation and may contribute to injury, yet the detailed signaling mechanisms leading to such a response are not well understood. Herein we tested the hypothesis that myocardial ischemia activates interleukin receptor-associated kinase-1 (IRAK-1), a kinase critical for the innate immune signaling such as that of Toll-like receptors (TLRs), via a mechanism that involves heat shock proteins (HSPs) and TLRs. Coronary artery occlusion induced a rapid myocardial IRAK-1 activation within 30 min in wild-type (WT), TLR2(-/-), or Trif(-/-) mice, but not in TLR4(def) or MyD88(-/-) mice. HSP60 protein was markedly increased in serum or in perfusate of isolated heart following ischemia/reperfusion (I/R). In vitro, recombinant HSP60 induced IRAK-1 activation in cells derived from WT, TLR2(-/-), or Trif(-/-) mice, but not from TLR4(def) or MyD88(-/-) mice. Both myocardial ischemia- and HSP60-induced IRAK-1 activation was abolished by anti-HSP60 antibody. Moreover, HSP60 treatment of cardiomyocytes (CMs) led to marked activation of caspase-8 and -3, but not -9. Expression of dominant-negative mutant of Fas-associated death domain protein or a caspase-8 inhibitor completely blocked HSP60-induced caspase-8 activation, suggesting that HSP60 likely activates an apoptotic program via the death-receptor pathway. In vivo, I/R-induced myocardial apoptosis and cytokine expression were significantly attenuated in TLR4(def) mice or in WT mice treated with anti-HSP60 antibody compared with WT controls. Taken together, the current study demonstrates that myocardial ischemia activates an innate immune signaling via HSP60 and TLR4, which plays an important role in mediating apoptosis and inflammation during I/R.
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PMID:Myocardial ischemia activates an injurious innate immune signaling via cardiac heat shock protein 60 and Toll-like receptor 4. 2177 38

Increasing incidence of small intestinal ulcers associated with nonsteroidal anti-inflammatory drugs (NSAIDs) has become a topic with recent advances of endoscopic technology. However, the pathogenesis and therapy are not fully understood. The aim of this study is to examine the effect of Rikkunshito (TJ-43), a traditional herbal medicine, on expression of HSP60 and cytoprotective ability in small intestinal cell line (IEC-6). Effect of TJ-43 on HSP60 expression in IEC-6 cells was evaluated by immunoblot analysis. The effect of TJ-43 on cytoprotective abilities of IEC-6 cells against hydrogen peroxide or indomethacin was studied by MTT assay, LDH-release assay, caspase-8 activity, and TUNEL. HSP60 was significantly induced by TJ-43. Cell necrosis and apoptosis were significantly suppressed in IEC-6 cells pretreated by TJ-43 with overexpression of HSP60. Our results suggested that HSP60 induced by TJ-43 might play an important role in protecting small intestinal epithelial cells from apoptosis and necrosis in vitro.
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PMID:Traditional Herbal Medicine, Rikkunshito, Induces HSP60 and Enhances Cytoprotection of Small Intestinal Mucosal Cells as a Nontoxic Chaperone Inducer. 2182 40