Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Abnormal accumulation of disease-causing protein is a commonly observed characteristic in chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and polyglutamine (polyQ) diseases. A therapeutic approach that could selectively eliminate would be a promising remedy for neurodegenerative disorders. Spinal and bulbar muscular atrophy (SBMA), one of the polyQ diseases, is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. The pathogenic gene product is polyQ-expanded androgen receptor (AR), which belongs to the heat shock protein (Hsp) 90 client protein family. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a novel Hsp90 inhibitor, is a new derivative of geldanamycin that shares its important biological activities but shows less toxicity. 17-AAG is now in phase II clinical trials as a potential anti-cancer agent because of its ability to selectively degrade several oncoproteins. We have recently demonstrated the efficacy and safety of 17-AAG in a mouse model of SBMA. The administration of 17-AAG significantly ameliorated polyQ-mediated motor neuron degeneration by reducing the total amount of mutant AR. 17-AAG accomplished the preferential reduction of mutant AR mainly through Hsp90 chaperone complex formation and subsequent proteasome-dependent degradation. 17-AAG induced Hsp70 and Hsp40 in vivo as previously reported; however, its ability to induce HSPs was limited, suggesting that the HSP induction might support the degradation of mutant protein. The ability of 17-AAG to preferentially degrade mutant protein would be directly applicable to SBMA and other neurodegenerative diseases in which the disease-causing proteins also belong to the Hsp90 client protein family. Our proposed therapeutic approach, modulation of Hsp90 function by 17-AAG treatment, has emerged as a candidate for molecular-targeted therapies for neurodegenerative diseases. This review will consider our research findings and discuss the possibility of a clinical application of 17-AAG to SBMA and other neurodegenerative diseases.
J Mol Med (Berl) 2006 Aug
PMID:Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein. 1674 51

1. We investigated the immunohistochemical alterations of BDNF, NGF, HSP 70 and ubiquitin in the hippocampus 1 h to 14 days after transient cerebral ischemia in gerbils. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor pitavastatin against the changes of BDNF, NGF, HSP 70 and ubiquitin in the hippocampus after cerebral ischemia in the hippocampus after ischemia. 2. The transient cerebral ischemia was carried out by clamping the carotid arteries with aneurismal clips for 5 min. 3. In the present study, the alteration of HSP 70 and ubiquitin immunoreactivity in the hippocampal CA1 sector was more pronounced than that of BDNF and NGF immunoreactivity after transient cerebral ischemia. In double-labeled immunostainings, BDNF, NGF and ubiquitin immunostaining was observed both in GFAP-positive astrocytes and MRF-1-positive microglia in the hippocampal CA1 sector after ischemia. Furthermore, prophylactic treatment with pitavastatin prevented the damage of neurons with neurotrophic factor and stress proteins in the hippocampal CA1 sector after ischemia. 4. These findings suggest that the expression of stress protein including HSP 70 and ubiquitin may play a key role in the protection against the hippocampal CA1 neuronal damage after transient cerebral ischemia in comparison with the expression of neurotrophic factor such as BDNF and NGF. The present findings also suggest that the glial BDNF, NGF and ubiquitin may play some role for helping surviving neurons after ischemia. Furthermore, our present study indicates that prophylactic treatment with pitavastatin can prevent the damage of neurons with neurotrophic factor and stress proteins in the hippocampal CA1 sector after transient cerebral ischemia. Thus our study provides further valuable information for the pathogenesis after transient cerebral ischemia.
Cell Mol Neurobiol 2007 Mar
PMID:Postischemic alterations of BDNF, NGF, HSP 70 and ubiquitin immunoreactivity in the gerbil hippocampus: pharmacological approach. 1681 May 63

The chloroplast HSP100/ClpB is a newly documented member of the ClpB family, but little was known about its role in imparting thermotolerance to cells. A cDNA coding for a HSP100/ClpB homolog has been cloned from Lycopersicon esculentum and termed as Lehsp100/ClpB (the cDNA sequence of Lehsp100/ClpB has been submitted to the GenBank database under accession number: AB219939). The protein encoded by the cDNA was most similar to the putative chloroplast HSP100/ClpBs in higher plants and the ClpB from Cyanobacterium Synechococcus sp. A 97 kDa protein, which matched the predicted size of mature LeHSP100/ClpB, was immunologically detected in chloroplast isolated from heat-treated tomato plants. In addition, the fusion protein, combining the transit sequence of LeHSP100/ClpB and GFP, was found to be located in chloroplast based on the observations of fluorescent microscope images. These results indicated the chloroplast-localization of LeHSP100/ClpB. Both the transcript and the protein of Lehsp100/ClpB were not detected under normal growth conditions, but they were induced by increasingly higher temperatures. An antisense Lehsp100/ClpB cDNA fragment was introduced into the tomato by Agrobacterium-mediated transformation. Antisense lines exhibited an extreme repression of heat-induced expression of Lehsp100/ClpB. The levels of chloroplast HSP60 and small HSP in antisense lines were identical to those of the control plants. After plants preconditioned at 38 degrees C for 2 h were exposed to a lethal heat shock at 46 degrees C for 2 h, the antisense lines were greatly impaired and withered in 21 days of the recovery phase, whereas the untransformed control plants and the vector-transformed plants survived. Furthermore, chlorophyll fluorescence measurements showed that PS II in antisense lines were more susceptible to the thermal irreversible inactivation than the untransformed and vector-transformed control plants. This work provides the first example that induction of chloroplast LeHSP100/ClpB contributes to the acquisition of thermotolerance in higher plants.
Plant Mol Biol 2006 Oct
PMID:The involvement of chloroplast HSP100/ClpB in the acquired thermotolerance in tomato. 1691 11

University of Oldenburg, Department of Biology, Molecular Neurobiology, D-26111 Oldenburg, Germany Ubiquitinated tau-positive inclusion bodies in oligodendrocytes are consistent features in a variety of neurodegenerative disorders, and their formation points to an underlying incapacity of the protein quality control system that normally prevents the accumulation of misfolded proteins. To study the consequences of proteasomal impairment, we have used an oligodendroglial cell line, namely OLN-t40 cells, genetically engineered to express the longest human tau isoform. Treatment of OLN-t40 cells with the proteasomal inhibitor MG-132 (0.5 microM, 18 h) caused the formation of large, nonfibrillary tau-positive aggregates containing the small HSP alphaB-crystallin and ubiquitin in the vicinity of the microtubule organizing center (MTOC). The sequestration of misfolded proteins into specialized regions, called aggresomes, in response to stress stimuli has been reported to be associated with a redistribution of intermediate filaments (IFs). In oligodendroglial cells, which do not contain a cytoplasmic IF system, aggresomelike inclusions were instead surrounded by bundles of MTs and contained clusters of mitochondria. Aggresome formation was prevented by both MT-stabilizing and -destabilizing drugs, indicating not only that an intact cytoskeleton but also the dynamic instability of the MT network is required. Furthermore, the binding of stress-induced alphaBcrystallin to the MTs points to a possible protective role during disease progression.
J Mol Neurosci 2006
PMID:The dynamic instability of microtubules is required for aggresome formation in oligodendroglial cells after proteolytic stress. 1695 5

In previous studies, the only small HSPs that have been studied in Xenopus laevis are members of the HSP30 family. We now report the analysis of Xenopus HSP27, a homolog of the human small HSP, HSP27. To date the presence of both hsp30 and hsp27 genes has been demonstrated only in minnow and chicken. Xenopus HSP27 cDNA encodes a 213 aa protein that contains an alpha-crystallin domain as well as a polar C-terminal extension. Xenopus HSP27 shares 71% identity with chicken HSP24 but only 19% identity with Xenopus HSP30C. Northern blot analysis revealed that Xenopus HSP27 gene expression was developmentally regulated. Constitutive and heat shock-induced hsp27 mRNA accumulation was first detectable at the early tailbud stage while HSP27 protein was detected at the tadpole stage. Furthermore, hsp27 mRNA was enriched in selected tissues under both control and heat shock conditions. Whole mount in situ hybridization analysis detected the presence of this message in the lens vesicle, heart, head, somites, and tail region. Purified recombinant HSP27 protein displayed molecular chaperone properties since it had the ability to inhibit heat-induced aggregation of target proteins including citrate synthase, malate dehydrogenase and luciferase. Thus, Xenopus HSP27, like HSP30, is a developmentally-regulated heat-inducible molecular chaperone.
Comp Biochem Physiol A Mol Integr Physiol 2007 May
PMID:Analysis of the expression and function of the small heat shock protein gene, hsp27, in Xenopus laevis embryos. 1726 55

Expression of inducible heat shock protein (HSP70) requires activation of heat shock transcription factor-1 (HSF-1). Recent evidence suggests that interleukin-6 (IL-6) can modify the response of HSF-1 to heat. We hypothesized that IL-6 would prime the HSP response by causing de-repression of HSF-1 resulting in augmented HSP expression in stressed cells. In this study we show that IL-6 has no direct effect on HSP70 expression at 37 degrees C but does augment HSP70 expression in response to heat. IL-6 treatment decreased active MAPK/pERK and glycogen synthase kinase 3beta (GSK3beta) expression and GSK3beta kinase activity. In IL-6-treated cells, monomeric HSF-1 accumulated in the cytoplasm and nucleus, bound DNA but was transcriptionally inactive. On exposure to heat shock this modified monomer assumed the transcriptionally active phenotype with trimerization and hyperphosphorylation evident. The increased induction of HSP70 in IL-6 and heat-treated cells was inhibited using PI3-kinase inhibitors or Akt inhibition and was HSF-1 dependent. IL-6, via the PI3-kinase/Akt pathway leads to inhibition of the repressive kinases MAPK/pERK and GSK3beta, and this converts inactive HSF-1 to an intermediate DNA-binding form augmenting transcriptional activation in the presence of a second stressor.
Int J Mol Med 2007 Mar
PMID:De-repression of heat shock transcription factor-1 in interleukin-6- treated hepatocytes is mediated by downregulation of glycogen synthase kinase 3beta and MAPK/ERK-1. 1727 89

The existing literature indicates a crucial role of p38 MAP (mitogen-activated protein) kinase (p38MAPK) and its downstream target MAPKAP kinase 2 (MK2) in ischemic preconditioning (IPC). Accordingly, deletion of MK2 gene should abolish the cardioprotective ability of IPC. Interestingly, we were able to partially precondition the hearts from MK2(-/-) knockout mice suggesting the existence of an as yet unknown alternative downstream target of p38MAPK. A recent study from our laboratory also determined a crucial role of CREB (cyclic AMP response element binding protein) in IPC. Since CREB is a downstream target of MSK-1 (mitogen- and stress-activated protein kinase-1) situated at the crossroad of ERK (extracellular receptor kinase) and p38MAPK signaling pathways, we reasoned that MSK-1 could be a downstream molecular target for p38MAPK and ERK signaling in the IPC hearts. To test this hypothesis, the rat hearts were subjected to IPC by four cyclic episodes of 5 min ischemia and 10 min reperfusion. As expected, IPC induced the activation of ERK1/2, p38MAPK, MK2 and HSP (heat shock protein) 27 as evidenced by their increased phosphorylation; and the inhibition of p38MAPK with SB203580 almost completely, and the inhibition of ERK1/2 with PD098059 partially, abolished cardioprotective effects of IPC. Inhibition of MSK-1 with short hairpin RNA (shRNA) also abolished the IPC-induced cardioprotection. SB203580 partially blocked the effects of MSK-1 suggesting that MSK-1 sits downstream of p38MAPK. shRNA-MSK-1 blocked the contribution of both p38MAPK and ERK1/2 as it is uniquely situated at the downstream crossroad of both of these MAP kinases. Although MSK-1 sits downstream of both ERK1/2 and p38MAPK, ERK1/2 activation appears to play less significant role compared to p38MAPK, since its inhibition blocked MSK activation only partially. Consistent with these results, shRNA-MSK-1 blocked the partial PC in MK2(-/-) hearts, and in combination with SB203580, completely abolished the PC effects in the wild-type hearts. The IPC-induced survival signaling was almost completely inhibited with SB203580, and only partially with PD 098059 as evidenced from the inhibition patterns of IPC induced activation of CREB, Akt and Bcl-2. Again SB203580 alone or in combination with shRNA-MSK-1 inhibited IPC induced survival signal comparatively, suggesting that MSK-1 exists downstream of p38MAPK. Taken together, these results indicate for the first time MSK-1 as an alternative (other than MK2) downstream target for p38MAPK, which also transmits survival signal through the activation of CREB.
J Mol Cell Cardiol 2007 May
PMID:Ischemic preconditioning involves dual cardio-protective axes with p38MAPK as upstream target. 2323 Jun 4

In many forms of congenital heart disease, the right ventricle (RV) is subject to abnormal loading conditions resulting in RV hypertrophy and remodeling. We determined the alterations in RV cytoplasmic proteomic phenotype that occur during prolonged periods of RV pressure overload. We performed a differential proteomic profiling study on RV hypertrophy using an animal model of various durations of pulmonary artery banding (PAB) in parallel with hemodynamic characterization. This hemodynamic evaluation showed that after 6, 12 and 20 weeks of PAB, the RV is in a compensated state of hypertrophy. Overall, the majority of protein changes were metabolism related indicating a shift towards the glycolytic pathway at the expense of beta-oxidation in the RV of the PAB animals. The changes in proteins related to the glycolytic pathway, exemplified by enolase and creatine kinase B-chain, tended to precede changes in beta-oxidation. In parallel, increases in stress chaperones, exemplified by several phosphorylated HSP-27 species, are present from the 6 week time point, whereas increases in antioxidant proteins, exemplified by peroxiredoxin 2 and 6, appear to be restricted to the 12 week time point. The p38 MAPK signal transduction pathway appears not to be activated. Observed protein changes are likely part of a protective mechanism against the development of RV failure.
J Mol Cell Cardiol 2007 Aug
PMID:Time dependent changes in cytoplasmic proteins of the right ventricle during prolonged pressure overload. 1760 72

Geranylgeranylacetone (GGA), an antiulcer agent, has the ability to induce 70-kDa heat shock protein (HSP70) in various cell types and to protect cells from apoptogenic insults. However, little is known about effects of GGA on other HSP families of molecules. We found that, at concentrations >/=100 microM, GGA caused selective expression of 78-kDa glucose-regulated protein (GRP78), an HSP70 family member inducible by endoplasmic reticulum (ER) stress, without affecting the level of HSP70 in various cell types. Induction of ER stress by GGA was also evidenced by expression of another endogenous marker, CCAAT/enhancer-binding protein-homologous protein (CHOP); decreased activity of ER stress-responsive alkaline phosphatase; and unfolded protein response (UPR), including activation of the activating transcription factor 6 (ATF6) pathway and the inositol-requiring ER-to-nucleus signal kinase 1-X-box-binding protein 1 (IRE1-XBP1) pathway. Incubation of mesangial cells with GGA caused significant apoptosis, which was attenuated by transfection with inhibitors of caspase-12 (i.e., a dominant-negative mutant of caspase-12 and MAGE-3). Dominant-negative suppression of IRE1 or XBP1 significantly attenuated apoptosis without affecting the levels of CHOP and GRP78. Inhibition of c-Jun NH(2)-terminal kinase, the molecule downstream of IRE1, by 1,9-pyrazoloanthrone (SP600125) did not improve cell survival. Blockade of ATF6 by 4-(2-aminoethyl) benzenesulfonyl fluoride enhanced apoptosis by GGA, and it was correlated with attenuated induction of both GRP78 and CHOP. Overexpression of GRP78 or dominant-negative inhibition of CHOP significantly attenuated GGA-induced apoptosis. These results suggested that GGA triggers both proapoptotic (IRE1-XBP1, ATF6-CHOP) and antiapoptotic (ATF6-GRP78) UPR and thereby coordinates cellular fate even without induction of HSP70.
Mol Pharmacol 2007 Nov
PMID:Geranylgeranylacetone, an inducer of the 70-kDa heat shock protein (HSP70), elicits unfolded protein response and coordinates cellular fate independently of HSP70. 1770 88

Heat stress is a major constraint to wheat production and negatively impacts grain quality, causing tremendous economic losses, and may become a more troublesome factor due to global warming. At the cellular level, heat stress causes denaturation and aggregation of proteins and injury to membranes leading to alterations in metabolic fluxes. Protein aggregation is irreversible, and protection of proteins from thermal aggregation is a strategy a cell uses to tolerate heat stress. Here we report on the development of transgenic wheat (Triticum aestivum) events, expressing a maize gene coding for plastidal protein synthesis elongation factor (EF-Tu), which, compared to non-transgenic plants, display reduced thermal aggregation of leaf proteins, reduced heat injury to photosynthetic membranes (thylakoids), and enhanced rate of CO(2) fixation after exposure to heat stress. The results support the concept that EF-Tu ameliorates negative effects of heat stress by acting as a molecular chaperone. This is the first demonstration of the introduction of a plastidal EF-Tu in plants that leads to protection against heat injury and enhanced photosynthesis after heat stress. This is also the first demonstration that a gene other than HSP gene can be used for improvement of heat tolerance and that the improvement is possible in a species that has a complex genome, hexaploid wheat. The results strongly suggest that heat tolerance of wheat, and possibly other crop plants, can be improved by modulating expression of plastidal EF-Tu and/or by selection of genotypes with increased endogenous levels of this protein.
Plant Mol Biol 2008 Oct
PMID:Heterologous expression of a plastid EF-Tu reduces protein thermal aggregation and enhances CO2 fixation in wheat (Triticum aestivum) following heat stress. 1862 33


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