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Biomedical subjects

P Csermely

Publications and source records attributed to P Csermely.

At least 37 records · Page 2Linked to original sources
PubMed2000

Steroid receptor and molecular chaperone encounters in the nucleus.

Steroid hormone receptors interact with several different molecular chaperones. DeFranco and Csermely discuss how the molecular chaperones p23 and Hsp90 may serve to regulate the activity of the ligand-bound steroid receptors within the nucleus. The authors hypothesize that these chaperone proteins may have a proactive role in promoting recycling of receptors once they have interacted with chromatin and in allowing rebinding of ligand once the receptors have been recycled.

Cell Nucleus↗
PubMed2000

Research training between 14 and 18 in Hungary.

The first five years of a new program to organize high-level scientific research training for gifted high school students in Hungary are described. Besides giving unique research opportunities for talented students in their most receptive age, the program already helped the establishment of almost 100 scientific research clubs in Hungarian high schools, provided a focal point for science training of high school teachers and helped regional cooperation in Central-Eastern Europe.

Journal Article↗
PubMed2000

Molecular chaperones and the aging process.

Molecular chaperones are abundant, well-conserved proteins responsible for the maintenance of the conformational homeostasis of cellular proteins and RNAs. Environmental stress is a proteotoxic insult to the cell, which leads to chaperone (heat shock protein, stress protein) induction. The protective role of chaperones is a key factor for cell survival and in repairing cellular damage. The present review summarizes our current knowledge about changes in chaperone expression and function in the aging process, as well as their possible involvement in the development of longevity and cellular senescence. We also overview their putative role in neurodegenerative diseases, such as in Alzheimer's disease and the changes in immune and autoimmune response against various chaperones in aging.

Aging↗
PubMed2000

The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation.

The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin geldanamycin. In this study, we demonstrate that geldanamycin treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, geldanamycin decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. Geldanamycin also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with geldanamycin, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by geldanamycin, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation.

Acyltransferases↗
PubMed1999

Mammalian Hsp70 and Hsp110 proteins bind to RNA motifs involved in mRNA stability.

In this study, in vitro RNA binding by members of the mammalian 70-kDa heat shock protein (Hsp) family was examined. We show that Hsp/Hsc70 and Hsp110 proteins preferentially bound AU-rich RNA in vitro. Inhibition of RNA binding by ATP suggested the involvement of the N-terminal ATP-binding domain. By using deletion mutants of Hsp110 protein, a diverged Hsp70 family member, RNA binding was localized to the N-terminal ATP-binding domain of the molecule. The C-terminal peptide-binding domain did not bind RNA, but its engagement by a peptide substrate abrogated RNA binding by the N terminus of the protein. Interestingly, removal of the C-terminal alpha-helical structure or the alpha-loop domain unique to Hsp110 immediately downstream of the peptide-binding domain, but not both, resulted in considerably increased RNA binding as compared with the wild type protein. Finally, a 70-kDa activity was immunoprecipitated from RNA-protein complexes formed in vitro between cytoplasmic proteins of human lymphocytes and AU-rich RNA. These findings support the idea that certain heat shock proteins may act as RNA-binding entities in vivo to guide the appropriate folding of RNA substrates for subsequent regulatory processes such as mRNA degradation and/or translation.

3' Untranslated Regions↗
PubMed1999

Chaperone-percolator model: a possible molecular mechanism of Anfinsen-cage-type chaperones.

Although we have a rather elaborate "working-cycle" for the 60 kDa molecular chaperones, which possess a cavity, and are called Anfinsen-cage-type chaperones to emphasize that they provide a closed, protected environment to help the folding of their substrates, our understanding of the molecular mechanism of how these chaperones help protein folding is still incomplete. The present study adds two novel elements to the mechanism of how Anfinsen-cage-type chaperones (members of the 60 kDa chaperone family) aid protein folding. It is proposed that (1) these chaperones do not generally unfold their targets, but by a multidirectional expansion preferentially loosen the tight, inner structure of the collapsed target protein; and (2) during the expansion water molecules enter the hydrophobic core of the target, this percolation being a key step in chaperone action. This study compares this chaperone-percolator model with existing explanations and suggests further experiments to test it. BioEssays 1999;21:959-965.

Chaperonin 60↗
PubMed1999

Interactions of Hsp90 with histones and related peptides.

The 90 kDa heat shock protein (Hsp90) induces the condensation of the chromatin structure [Csermely, P., Kajtár, J., Hollósi, M., Oikarinen, J., and Somogyi, J. (1994) Biochem. Biophys. Res. Commun. 202, 1657-1663]. In our present studies we used surface plasmon resonance measurements to demonstrate that Hsp90 binds histones H1, H2A, H2B, H3 and H4 with high affinity having dissociation constants in the submicromolar range. Strong binding of the C-terminal peptide of histone H1 containing the SPKK-motif and a pentaeicosa-peptide including the Hsp90 bipartite nuclear localization signal sequence was also observed. However, a lysine/arginine-rich peptide of casein, and the lysine-rich platelet factor 4 did not display a significant interaction with Hsp90. Histones and positively charged peptides modulated the Hsp90-associated kinase activity. Interactions between Hsp90, histones, and high mobility group (HMG) protein-derived peptides raise the possibility of the involvement of Hsp90 in chromatin reorganization during steroid action, mitosis, or after cellular stress.

Amino Acid Sequence↗
PubMed1999

Acetylcholine-induced phosphorylation in isolated outer hair cells.

Two groups of isolated, surviving outer hair cells (OHCs) of guinea pig cochleas (n = 20, for each group) were treated with 10 microM acetylcholine or acetylcholine plus strichnine (an alpha9 nAChR antagonist), respectively, under short-term tissue culture conditions. The protein content of the cell homogenates was separated by SDS-polyacrylamide gel electrophoresis, Western blotted and labelled with an antibody against phosphoserine residues. Signals were detected using the ECL system. Acetylcholine challenge of the OHCs resulted in a difference in the pattern of phosphorylated proteins from those of strichnine pretreated cells. A 220 kDa and a 120 kDa protein expressed a more intense phosphorylated state in the ACh group compared with the ACh plus strichnine group. The 220 kDa phosphoprotein is in the range of the cytoskeletal protein beta-fodrin, whereas the 120 kDa fraction is similar to alpha-fodrin or an ankyrin isoform. Phosphorylation of proteins due to activation of the AChR by agonist can play a role in the signalling mechanism between receptor activation and increase in the electromotile capability of isolated OHCs.

Acetylcholine↗
PubMed1998

Interaction of vanadate oligomers and permolybdate with the 90-kDa heat-shock protein, Hsp90.

The 90-kDa heat-shock protein (Hsp90) is a molecular chaperone that aids the folding of nuclear hormone receptors and protein kinases. Hsp90 x protein complexes can be stabilized by molybdate and by other transition metal oxyanions such as vanadate. Our earlier findings [Csermely, P., Kajtár, J., Hollósi, M., Jalsovszky, G., Holly, S., Kahn, C. R., Gergely, P. Jr, Söti, C., Mihály, K. & Somogyi, J. (1993) J. Biol. Chem. 268, 1901-1907] showed that vanadate and molybdate can induce a large conformational change of Hsp90. Here we provide direct evidence for the binding of vanadate and molybdate to Hsp90 by demonstrating that surface-plasmon-resonance measurements indicate binding of various vanadate oligomers to Hsp90. 51V-NMR measurements show an extensive interaction of decavanadate with the chaperone, and permolybdate treatment of Hsp90 induces a marked mobility shift of the protein and its tryptic fragments. Our results indicate the flexibility of molybdate/vanadate-binding sites of Hsp90, which are able to accommodate various species of these transition metal anions.

Amino Acid Sequence↗
PubMed1998

Molecular chaperones in the etiology and therapy of cancer.

Molecular chaperones are ubiquitous, well-conserved proteins that account for 2-5 % of all cellular proteins in most cells. The present review summarizes our current knowledge about their involvement in the etiology and therapy of cancer with special emphasis on the expression of chaperones in malignant cells, their role in folding of (proto)oncogene products, cell cycle regulation, cell differentiation and apoptosis, development of metastasis, and their participation in the recognition of malignant cells. We also overview the importance of chaperones in hyperthermia, drug resistance, and recent approaches in chaperone-immunotherapy.

Animals↗
PubMed1998

Attenuation of diabetic retinopathy by the molecular chaperone-inducer amino acid analogue canavanine in streptozotocin-diabetic rats.

The effect of canavanine treatment on the electroretinograms of healthy and streptozotocin-diabetic rats was studied. The characteristic amplitudes of the a-wave, W2 and W3 oscillatory potentials were markedly diminished in the 2-week streptozotocin-diabetic rats compared with those of the control rats. In contrast, the amplitudes of all the responses of the canavanine-pretreated streptozotocin-diabetic rats were practically indistinguishable from those of the control animals. Our results prompt further investigations for the use of amino acid analogues and other inducers of molecular chaperones in easing the chronic consequences of diabetes such as retinopathy.

Animals↗
PubMed1998

The Hsp90-specific inhibitor, geldanamycin, blocks CD28-mediated activation of human T lymphocytes.

The 90 kDa heat shock protein (Hsp90) is a molecular chaperone aiding the folding of nuclear hormone receptors and protein kinases. Hsp90-mediated folding can be disrupted by the Hsp90-specific drug, geldanamycin. Here we provide evidence for the inhibition of the CD28-specific BW 828 antibody-mediated activation of human T lymphocyte proliferation, IL-2 secretion and IL-2 receptor expression by geldanamycin. Our results suggest that the major cytoplasmic chaperone, Hsp90, plays an important role in CD28-mediated T lymphocyte activation.

Antibodies, Blocking↗
PubMed1998

The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review.

The 90-kDa molecular chaperone family (which comprises, among other proteins, the 90-kDa heat-shock protein, hsp90 and the 94-kDa glucose-regulated protein, grp94, major molecular chaperones of the cytosol and of the endoplasmic reticulum, respectively) has become an increasingly active subject of research in the past couple of years. These ubiquitous, well-conserved proteins account for 1-2% of all cellular proteins in most cells. However, their precise function is still far from being elucidated. Their involvement in the aetiology of several autoimmune diseases, in various infections, in recognition of malignant cells, and in antigen-presentation already demonstrates the essential role they likely will play in clinical practice of the next decade. The present review summarizes our current knowledge about the cellular functions, expression, and clinical implications of the 90-kDa molecular chaperone family and some approaches for future research.

Animals↗
PubMed1997

Changes in the expression of Na+/K+-ATPase isoenzymes in the left ventricle of diabetic rat hearts: effect of insulin treatment.

Na+/K+-ATPase related strophanthidin sensitive 3-O-methylfluorescein-phosphatase activity, [3H]ouabain binding and expression of Na+/K+-ATPase subunit isoforms were measured in the left ventricle of the heart of normal and streptozotocin-diabetic rats with and without insulin treatment. Compared to control animals, the enzyme activity was 0.75 +/- 0.09 and 0.62 +/- 0.06 times lower in rats diabetic for 2 and for 4 weeks, respectively. This was associated with a proportional decrease of the [3H]ouabain binding sites. Immunoblots indicated a 0.76 +/- 0.08 and 0.61 +/- 0.08-fold decrease of alpha1, a 0.68 +/- 0.09 and 0.41 +/- 0.04-fold decrease of alpha2 subunit in 2- and 4-week diabetic rats, respectively relative to controls. Beta1 subunit decreased proportionally 0.71 +/- 0.07 and 0.38 +/- 0.06-fold, and beta2 decreased 0.75 +/- 0.08 and 0.31 +/- 0.06-fold, respectively. Northern blot analysis revealed a significant reduction in mRNA level of Na+/K+-ATPase subunit isoforms after 2 and 4 weeks of diabetes (for alpha1 66.2 +/- 8.2 and 55.9 +/- 7.8% of controls for alpha2 91.7 +/- 12.1 and 41.1 +/- 7.1% of controls and for beta subunit 93.4 +/- 11.1 and 49.8 +/- 6.8% of controls, respectively). Although, mRNA levels of isoform reverted to even higher levels than the control values after insulin treatment, insulin caused only a partial recovery of enzyme activity, [3H]ouabain binding capacity and protein expression. We have obtained evidence that in cardiac left ventricle there are more than one type of Na+/K+-ATPase alpha and beta subunit isoforms which are affected in diabetes and by insulin treatment. The time course of diabetes induced changes and the degree of involvement suggest that the Na+/K+-ATPase isoforms are altered individually.

Animals↗
PubMed1997

Binding affinity of proteins to hsp90 correlates with both hydrophobicity and positive charges. A surface plasmon resonance study.

The 90 kDa heat shock protein (hsp90) is a major cytoplasmic molecular chaperone associating with numerous other proteins including steroid receptors. Here we provide the first numerical analysis of hsp90-target associations using surface plasmon resonance. Binding affinities of histones, the "native molten globule", casein and calmodulin to hsp90 decrease in the order of Kd = 70 +/- 24, 220 +/- 70 and 1800 +/- 600 nM, respectively. Analysis of the structure of binding proteins revealed that their binding affinity depends on both hydrophobicity and positive charges making the discriminative features of hsp90 similar to those of other molecular chaperones.

Adenosine Triphosphate↗