Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most heat shock proteins (HSPs) have pro-survival functions. However, the role of HSP60, a mitochondrial matrix protein, is somewhat controversial with both pro-survival and pro-apoptotic functions reported. Here we show that in numerous apoptotic systems HSP60 protein accumulates in the cytosol. In BMD188-induced cell death, HSP60 accumulates in the cytosol with significant mitochondrial release. In contrast, in apoptosis induced by multiple other inducers, the cytosolic HSP60 accumulates without an apparent mitochondrial release. The short interfering RNA-mediated knockdown experiments revealed that in BMD188-induced apoptosis, HSP60 has a pro-death function and that the pro-death role of HSP60 seems to involve caspase-3 maturation and activation in the cytosol. In contrast, HSP60 appears to play a pro-survival role in other apoptotic systems where there is no apparent mitochondrial release as its knockdown promotes cell death. In these latter apoptotic systems HSP60 does not associate with active caspase-3. In both cases, HSP60 does not appreciably interact with Bax. Taken together, our results suggest the following: 1) cytosolic accumulation of HSP60 represents a common phenomenon during apoptosis induction; 2) cytosolic HSP60 accumulation during apoptosis occurs either with or without apparent mitochondrial release; and 3) the cytosolically accumulated HSP60 possesses either pro-survival or pro-death functions, which involves differential interactions with caspase-3.
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PMID:Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3. 1782 27

Ouabain is Na(+)/K(+)-ATPase inhibitor and an endogenous regulator of blood pressure, it has dual effect on vascular endothelial cells(VEC) cell growth and VEC apoptosis is contributed to vascular dysfunction involved in vascular remolding. However, the precise mechanisms of apoptosis induced by ouabain remained unclear. The objective of this study was to identify the differently expressed proteins involved in VEC apoptosis induced by ouabain in order to explore cellular and subcellular mechanisms related to ouabain actions. Human umbilical vein endothelial cells (HUVEC) were exposed to increasing concentrations (0.1 nM to 10 microM) of ouabain at 12-48 h intervals. Cell viability tests revealed that high concentrations of ouabain inhibited cell growth. Flow cytometry and caspase-3 activity analysis confirmed that apoptosis was primarily responsible for ouabain induced cell death. Two-dimensional electrophoresis in conjunction with mass spectrometry revealed that the ouabain-induced apoptosis was accompanied by regulated expression of programmed cell death protein 6, cytochrome C1, endothelin converting enzyme, claudin-1, reticulon-4, galectin-1, ras-related protein rab-11B, calnexin, profilin-1 and heat shock protein 60 (HSP60). Further study on cytochrome c and HSP60 demonstrated that levels of mitochondria and cytosol cytochrome c and HSP60 changed in response to ouabain treatment. Data showed that mitochondria proteins such as HSP60 interferes with HSP60-Bax interactions played an important role in ouabain induced apoptosis. These data bring new sights into physiological role for ouabain in VEC apoptosis and vascular remodeling, thus provide new strategies for new anti-cardiovascular disease drug development or the identification of biomarkers for vascular dysfunction in ouabain related hypertension.
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PMID:Proteomics investigation of protein expression changes in ouabain induced apoptosis in human umbilical vein endothelial cells. 1824 27

Since an attenuated response to stress is a characteristic of senescence, a cellular senescence model was used to examine the mechanism of resistance against oxidative stress using human diploid fibroblasts (HDF). With increasing passage, the HDF showed increased production of reactive oxygen species (ROS). Late passage HDF were resistant to the lethal effects of oxidative stress, showing less cleavage of pro-caspase-3 and PARP than those of early ones. Since heat shock proteins (Hsps) are not only cytoprotective but also interfere with the apoptotic cascade, the expression patterns of Hsps during cellular senescence were next examined. Oxidative stress induced a decrease in the mitochondrial Hsp60 levels with a concomitant increase in the cytosolic Hsp60 levels in the early passage HDF, but not in late ones. To show that the resistance to oxidative stress is a specific effect of Hsp60, the levels of Hsp60 were knocked down by siRNA. As expected the Hsp60 knock-down cells were more resistant to oxidative stress. These findings show that Hsp60 is a key player in the resistance mechanism against oxidative stress and aging.
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PMID:Differential effect of oxidative stress on the apoptosis of early and late passage human diploid fibroblasts: implication of heat shock protein 60. 1839 35

Although digitalis has been used in clinical treatment extensively, the precise mechanism of its toxic actions on cardiovascular system remained unclear, it would be of interest to study the differential proteomic analysis of vascular endothelial cells in response to toxic concentrations of digitalis thus to provide new agents for treatment of digitalis-induced cytotoxicity. We employed human umbilical vein endothelial cells (HUVEC) as our model system. HUVEC were exposed to increasing concentrations (0.1 nM-10 microM) of digoxin at 12-96 h intervals. Cell viability tests revealed that digoxin played dual effects on cell growth. Apoptosis detection confirmed that apoptosis was primarily responsible for digoxin-induced cell death. Proteomics analysis further revealed that the digoxin-induced apoptosis was accompanied by regulated expression of ATP synthase beta chain, cystatin A, electron transfer flavoprotein, heterogeneous nuclear ribonucleoproteins H3, lamin A, profilin-1, proteasome subunit 5, succinyl-CoA ligase beta chain and heat shock protein 60 (HSP60). Deep study on the overexpression of HSP60 confirmed that HSP60 exerted a protective role in digoxin-induced apoptosis through inhibition of caspase-3 activity in HUVEC. These results provided an impetus for further delineation of mechanism of digoxin-induced cytotoxicity and offered new agents that help attenuate its toxicity.
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PMID:Comparative proteomics analysis reveals role of heat shock protein 60 in digoxin-induced toxicity in human endothelial cells. 1869 61

Freshwater turtles survive prolonged anoxia and reoxygenation without overt brain damage by well-described physiological processes, but little work has been done to investigate the molecular changes associated with anoxic survival. We examined stress proteins and apoptotic regulators in the turtle during early (1 h) and long-term anoxia (4, 24 h) and reoxygenation. Western blot analyses showed changes within the first hour of anoxia; multiple stress proteins (Hsp72, Grp94, Hsp60, Hsp27, and HO-1) increased while apoptotic regulators (Bcl-2 and Bax) decreased. Levels of the ER stress protein Grp78 were unchanged. Stress proteins remained elevated in long-term anoxia while the Bcl-2/Bax ratio was unaltered. No changes in cleaved caspase 3 levels were observed during anoxia while apoptosis inducing factor increased significantly. Furthermore, we found no evidence for the anoxic translocation of Bax from the cytosol to mitochondria, nor movement of apoptosis inducing factor between the mitochondria and nucleus. Reoxygenation did not lead to further increases in stress proteins or apoptotic regulators except for HO-1. The apparent protection against cell damage was corroborated with immunohistochemistry, which indicated no overt damage in the turtle brain subjected to anoxia and reoxygenation. The results suggest that molecular adaptations enhance pro-survival mechanisms and suppress apoptotic pathways to confer anoxia tolerance in freshwater turtles.
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PMID:Modulation of stress proteins and apoptotic regulators in the anoxia tolerant turtle brain. 1947 52

Though the fragile histidine triad gene product, Fhit, was discovered and characterized as a tumor suppressor 13 years ago, its sequence, structure, and cellular location did not provide clues to aid discovery of its mechanisms of suppression. Recently, using chemical cross-linkers and immunoprecipitation, a Fhit protein complex was identified that includes Hsp60 and Hsp10 which may mediate Fhit stability and mitochondrial localization, where Fhit binds and stabilizes ferredoxin reductase (Fdxr); when Fdxr is overexpressed, it can lead to production of reactive oxygen species (ROS) that induce apoptosis. Cancer cells expressing endogenous or exogenous Fhit, when exposed to H(2)O(2), an oxidative stress, produce higher levels of apoptosis-inducing ROS than matched, Fhit-negative cells; the Fhit-negative cancer cells survive, carrying DNA damage. In addition to this mitochondrial function, Fhit-overexpression in cancer cells exposed to replicative stress-inducing agents leads to enhanced caspase 3 activation and apoptosis, due to defective Chk1 activation. Thus, damage to the fragile FHIT locus leads to reduced expression of Fhit protein, and makes a two-pronged contribution to development of preneoplastic clonal expansion: (1) absence or reduction of Fhit leads to reduced expression of Fdxr and reduced ROS-induced apoptosis; (2) cells that escape ROS- or replicative stress-induced apoptosis can carry misrepaired DNA damage. The aberrant DNA damage response checkpoint in Fhit-deficient preneoplasias and cancers may make these lesions targets for inhibitors of proteins such as Parp1 and Chk1 with important roles in checkpoint responses, as observed for BRCA1-deficient cancer cells that also exhibit DNA damage repair deficiencies.
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PMID:Fragile gene product, Fhit, in oxidative and replicative stress responses. 1948 40

We recently reported that heat shock protein 60 (HSP60) via TLR4 signaling activates B cells and induces them to proliferate and secrete IL-10. We now report that HSP60 inhibits mouse B cell apoptosis, spontaneous or induced by dexamethasone or anti-IgM activation. Unlike HSP60 enhancement of B cell proliferation and IL-10 secretion, TLR4 signaling was not required for the inhibition of apoptosis by HSP60; nevertheless, MyD88 was essential. Inhibition of apoptosis by HSP60 was associated with up-regulation of the antiapoptotic molecules Bcl-2, Bcl-x(L), and survivin, maintenance of the mitochondrial transmembrane potential, and inhibition of caspase-3 activation. Moreover, B cells incubated with HSP60 manifested prolonged survival following transfer into recipient mice. These results extend the varied role of HSP60 in the innate regulation of the adaptive immune response.
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PMID:Heat shock protein 60, via MyD88 innate signaling, protects B cells from apoptosis, spontaneous and induced. 1956 Nov 2

This study was designed to estimate the toxic threshold of male and female fish to microcystins based on different biomarkers. Japanese medaka (Oryzias latipes) were fed dietary Microcystin-LR (0, 0.46, 0.85, 2.01 and 3.93 microg MC-LR/g dry diet for 8 weeks at 25 degrees C. The results revealed that dietary MC-LR inhibited growth at the end of 8 weeks. The survival of embryos and the RNA/DNA ratio of whole fish decreased significantly (P < 0.05) in fish fed 3.93 microg MC-LR/g dry diet. Heat shock protein (Hsp60) expression was induced in the liver of female and male fish fed diets containing > or =0.85 and 0.46 microg MC-LR/g diet, respectively. The activity of liver caspase 3/7 was significantly higher in female fish fed 3.93 microg MC-LR/g diet and in males fed 2.01 MC-LR microg/g dry diet than fish fed the control diet. The threshold for inhibition of liver protein phosphatase expression was lower in female (2.01 microg/g diet) than that in male fish (3.93 microg/g diet). Histopathological examination showed significant single-cell necrosis in female and male medaka fed diets containing 0.85 and 3.93 microg MC-LR/g diet, respectively. Based on different biomarkers, this study demonstrated that dietary MC-LR is toxic to Medaka and the effects are gender dependent.
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PMID:Toxic threshold of dietary microcystin (-LR) for quart medaka. 1994 79

Complex behavioural disabilities, as well as pain, characterise neuropathic pain conditions for which clinical treatment is sought. In rats, chronic constriction injury (CCI) of the sciatic nerve evokes, allodynia and hyperalgesia as well as three distinct patterns of disability, characterised by changes in social and sleep-wake behaviours: (i) Pain & Disability; (ii) Pain & Transient Disability and (iii) Pain alone. Importantly, the degree of allodynia and hyperalgesia is identical for each of these groups. Social-interactions and sleep-wake behaviours are regulated by neural networks, which converge on the periaqueductal grey (PAG). Rats with Pain & Disability show astrocyte activation restricted to the lateral and ventrolateral PAG. Reactive astrocytes are a hallmark of cell death (apoptosis and necrosis). Quantitative real-time RT-PCR for the mRNAs encoding Bax, Bcl-2, heat shock protein 60 (HSP60), mitogen activated kinase kinase (MEK2) and iNOS was performed on the dorsal midbrains of individual, disability characterised rats, extending our earlier Gene-Chip data, showing a select up-regulation of Bax and MEK2 mRNA, and a down-regulation of HSP60 mRNA, in Pain & Disability rats. The anatomical location of TUNEL and cleaved-caspase-3 immunoreactive profiles in the midbrain was also identified. Rats with Pain & Disability showed: (i) pro-apoptotic ratios of Bax:Bcl-2 mRNAs; (ii) decreased HSP60 mRNA; (iii) increased iNOS and MEK2 mRNAs; (iv) TUNEL-positive profiles in the lateral and ventrolateral PAG; and (v) caspase-3 immunoreactive neurons in the mesencephalic nucleus of the trigeminal nerve. Cell death in these specific midbrain regions may underlie the disabilities characterising this subgroup of nerve-injured rats.
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PMID:Evidence for cellular injury in the midbrain of rats following chronic constriction injury of the sciatic nerve. 2129 96

Caspases play a key role in the apoptotic pathway by virtue of their ability to cleave key protein substrates within the dying cell. Caspases are produced as inactive zymogens, and need to become proteolytically processed in order to become active. A key executioner caspase, caspase-3, has previously been found to exist in both the cytosol and the mitochondria. At the mitochondria, caspase-3 is associated with both the inner and outer mitochondrial membranes, where it interacts with heat shock proteins Hsp60 and Hsp10. Like caspase-3, a small portion of the p53 tumor suppressor protein is localized to mitochondria, particularly after genotoxic stress. p53 interacts with various members of the Bcl2 family at the mitochondria, and this interaction is key to its ability to induce apoptosis. In this study, we sought to determine the identity of other mitochondrial p53-interacting proteins. Using immunoprecipitation from purified mitochondria followed by mass spectrometry we identified caspase-3 as a mitochondrial p53-interacting protein. Interestingly, we find that tumor-derived mutant forms of p53 retain the ability to interact with mitochondrial caspase-3. Further, we find evidence that these mutant forms of p53 may interfere with the ability of procaspase-3 to become proteolytically activated by caspase-9. The combined data suggest that tumor-derived mutants of p53 may be selected for in tumor cells due to their ability to bind and inhibit the activation of caspase-3.
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PMID:Wild-type and mutant p53 proteins interact with mitochondrial caspase-3. 2132 76


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