Peter Csermely

Semmelweis University, Faculty of Medicine, Faculty Member

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The Wisdom of Networks: A General Adaptation and Learning Mechanism of Complex Systems

BioEssays

I hypothesize that re-occurring prior experience of complex systems mobilizes a fast response, wh... more I hypothesize that re-occurring prior experience of complex systems mobilizes a fast response, whose attractor is encoded by their strongly connected network core. In contrast, responses to novel stimuli are often slow and require the weakly connected network periphery. Upon repeated stimulus, peripheral network nodes remodel the network core that encodes the attractor of the new response. This "core-periphery learning" theory reviews and generalizes the heretofore fragmented knowledge on attractor formation by neural networks, periphery-driven innovation and a number of recent reports on the adaptation of protein, neuronal and social networks. The coreperiphery learning theory may increase our understanding of signaling, memory formation, information encoding and decision-making processes. Moreover, the power of network periphery-related "wisdom of crowds" inventing creative, novel responses indicates that deliberative democracy is a slow yet efficient learning strategy developed as the success of a billion-year evolution.

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Roles of heat shock factor 1 beyond the heat shock response

Cellular and molecular life sciences : CMLS, Jan 17, 2018

Various stress factors leading to protein damage induce the activation of an evolutionarily conse... more Various stress factors leading to protein damage induce the activation of an evolutionarily conserved cell protective mechanism, the heat shock response (HSR), to maintain protein homeostasis in virtually all eukaryotic cells. Heat shock factor 1 (HSF1) plays a central role in the HSR. HSF1 was initially known as a transcription factor that upregulates genes encoding heat shock proteins (HSPs), also called molecular chaperones, which assist in refolding or degrading injured intracellular proteins. However, recent accumulating evidence indicates multiple additional functions for HSF1 beyond the activation of HSPs. Here, we present a nearly comprehensive list of non-HSP-related target genes of HSF1 identified so far. Through controlling these targets, HSF1 acts in diverse stress-induced cellular processes and molecular mechanisms, including the endoplasmic reticulum unfolded protein response and ubiquitin-proteasome system, multidrug resistance, autophagy, apoptosis, immune response, ...

Are rapidly growing cancers more lethal?

European journal of cancer (Oxford, England : 1990), 2017

The view, that rapidly growing tumours are more likely than slow-growing tumours to metastasize a... more The view, that rapidly growing tumours are more likely than slow-growing tumours to metastasize and become lethal, has remained almost axiomatic for decades. Unaware of any solid evidence supporting this view, we undertook an exhaustive system-level analysis of intra- and intercellular signalling networks. This analysis indicated that rapid growth and metastasis are often different outcomes of complex integrated molecular events. Evidence from humans can be derived chiefly from screening interventions because interval cancers that surface clinically shortly after a negative screening test are, on average, more rapidly growing than cancers not detected by screening. We reviewed all available data limited to cancers of the breast, cervix and large bowel. The evidence from humans provides no support for the theory that rapidly growing cancers are more prone to metastasize. These findings indicate that the prevailing view should be reconsidered, as should the impact of length-biased sam...

Identification of critical paralog groups with indispensable roles in the regulation of signaling flow

Scientific Reports, 2016

Extensive cross-talk between signaling pathways is required to integrate the myriad of extracellu... more Extensive cross-talk between signaling pathways is required to integrate the myriad of extracellular signal combinations at the cellular level. Gene duplication events may lead to the emergence of novel functions, leaving groups of similar genes-termed paralogs-in the genome. To distinguish critical paralog groups (CPGs) from other paralogs in human signaling networks, we developed a signaling network-based method using cross-talk annotation and tissue-specific signaling flow analysis. 75 CPGs were found with higher degree, betweenness centrality, closeness, and 'bowtieness' when compared to other paralogs or other proteins in the signaling network. CPGs had higher diversity in all these measures, with more varied biological functions and more specific post-transcriptional regulation than non-critical paralog groups (non-CPG). Using TGF-beta, Notch and MAPK pathways as examples, SMAD2/3, NOTCH1/2/3 and MEK3/6-p38 CPGs were found to regulate the signaling flow of their respective pathways. Additionally, CPGs showed a higher mutation rate in both inherited diseases and cancer, and were enriched in drug targets. In conclusion, the results revealed two distinct types of paralog groups in the signaling network: CPGs and non-CPGs. Thus highlighting the importance of CPGs as compared to non-CPGs in drug discovery and disease pathogenesis.

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Neighbours of cancer-related proteins have key influence on pathogenesis and could increase the drug target space for anticancer therapies

npj Systems Biology and Applications, 2017

Even targeted chemotherapies against solid cancers show a moderate success increasing the need to... more Even targeted chemotherapies against solid cancers show a moderate success increasing the need to novel targeting strategies. To address this problem, we designed a systems-level approach investigating the neighbourhood of mutated or differentially expressed cancer-related proteins in four major solid cancers (colon, breast, liver and lung). Using signalling and protein-protein interaction network resources integrated with mutational and expression datasets, we analysed the properties of the direct and indirect interactors (first and second neighbours) of cancer-related proteins, not found previously related to the given cancer type. We found that first neighbours have at least as high degree, betweenness centrality and clustering coefficient as cancer-related proteins themselves, indicating a previously unknown central network position. We identified a complementary strategy for mutated and differentially expressed proteins, where the affect of differentially expressed proteins having smaller network centrality is compensated with high centrality first neighbours. These first neighbours can be considered as key, so far hidden, components in cancer rewiring, with similar importance as mutated proteins. These observations strikingly suggest targeting first neighbours as a novel strategy for disrupting cancer-specific networks. Remarkably, our survey revealed 223 marketed drugs already targeting first neighbour proteins but applied mostly outside oncology, providing a potential list for drug repurposing against solid cancers. For the very central first neighbours, whose direct targeting would cause several side effects, we suggest a cancer-mimicking strategy by targeting their interactors (second neighbours of cancer-related proteins, having a central protein affecting position, similarly to the cancer-related proteins). Hence, we propose to include first neighbours to network medicine based approaches for (but not limited to) anticancer therapies.

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Human Sirt protein-protein interaction network

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Chaperones come of age

Cell Stress and Chaperones, May 1, 2002

Chaperone function plays a key role in repairing proteotoxic damage, in the maintenance of cell a... more Chaperone function plays a key role in repairing proteotoxic damage, in the maintenance of cell architecture, and in cell survival. Here, we summarize our current knowledge about changes in chaperone expression and function in the aging process, as well as their involvement in longevity and cellular senescence. INTRODUCTION: CONVENTIONAL AND NONCONVENTIONAL ROLES OF MOLECULAR CHAPERONES

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Protein kinase C is involved in the early signals of interferon-α but not of interferon-γ in U937 cells

Journal of Interferon Research, 1990

Increasing interest is being focused on the role of protein kinase C (PKC) in the mode of action ... more Increasing interest is being focused on the role of protein kinase C (PKC) in the mode of action of interferons (IFNs). Here we report that IFN-a induced a transient translocation of PKC from the cytosol to the particulate fraction of U937 cells. In contrast, after IFN-7 treatment, no significant change in PKC activity could be observed. IFN-induced changes in membrane potential were also examined by means of a potential sensitive oxonol dye and flow cytometry. Hyperpolarization was induced by both IFN-a and IFN-7. The protein kinase inhibitor H-7 blocked the hyperpolarization induced by IFN-a but not by IFN-7. These concordant results suggest that PKC is involved in the early signals of IFN-a but not of IFN-7 in U937 cells.

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Limits of Scientific Growth

Science, Jun 1, 1999

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How to design multi-target drugs: Target search options in cellular networks

Expert Opin Drug Discov, Mar 4, 2007

Despite improved rational drug design and a remarkable progress in genomic, proteomic and highthr... more Despite improved rational drug design and a remarkable progress in genomic, proteomic and highthroughput screening methods, the number of novel, single-target drugs fell much behind expectations during the past decade. Multi-target drugs multiply the number of pharmacologically relevant target molecules by introducing a set of indirect, network-dependent effects. Parallel with this the low-affinity binding of multi-target drugs eases the constraints of druggability, and significantly increases the size of the druggable proteome. These effects tremendously expand the number of potential drug targets, and will introduce novel classes of multi-target drugs with smaller side effects and toxicity. Here we review the recent progress in this field, compare possible network attack strategies, and propose several methods to find target-sets for multi-target drugs.

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Hsp70 is present in human saliva

Medical Science Monitor International Medical Journal of Experimental and Clinical Research, Feb 1, 2003

Background: There is increasing evidence that chaperones are also present outside the cell, exert... more Background: There is increasing evidence that chaperones are also present outside the cell, exerting cytokine-like effects and influencing immune recognition. Hsp70 has been found to be present in human blood sera. Chaperonins Cpn10 and Cpn60 are present in pancreatic juice, but Hsp70 is not. These observations raise the possibility that molecular chaperones may be present in other secretory fluids, such as human saliva. Material/Methods: Human whole saliva was collected from six participants under resting conditions and secretory stimulation. The samples were precleared by centrifugation and sterile filtered. Salivary volume, protein concentration and amylase activity were determined. For detection of Hsp70 saliva proteins were separated on a 12.5% SDS-PAGE. Semi-dry Western blot analysis was used with a primary antibody against the inducible form of Hsp70. Hsp70 bands were detected with a horseradish peroxidase-linked secondary antibody and ECL-Western blotting analysis. Results: A single band was recognized around 70 kDa in the saliva of all the participants. There was a significant decrease of Hsp70, and a non-significant decrease of total protein concentration during stimulation, whereas the activity of salivary amylase increased significantly. Stimulation significantly increased the Hsp70, total protein and amylase outputs as well as the amylase/protein ratio, and decreased the Hsp70/amylase and Hsp70/protein ratios. Conclusions: Hsp70 is secreted to saliva, but unlike amylase is not transported by the exocytotic secretory mechanisms of acinar cells. Passive transport mechanisms of Hsp70 from blood serum or from salivary gland cells may be major routes of salivary Hsp70 secretion.

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Spondyloarthropathies and bone resorption: A possible role of heat shock protein (Hsp70): Review

Acta Physiologica Hungarica, Jul 1, 2009

Spondyloarthropathies consist of chronic inflammatory disorders genetically linked with each othe... more Spondyloarthropathies consist of chronic inflammatory disorders genetically linked with each other through HLA-B27 molecules, and are connected with the destruction of periarticular bone and also with systemic bone loss in many cases. Expected molecular mechanisms behind these conditions overlap the functions of Hsp70s, a group of major molecular chaperones and cytokines. Hsp70s may control disease progression via inhibition of unfolded HLA-B27 protein accumulation and alteration of ER stress signaling. Further, Hsp70s may improve disease related malfunction of antigen presentation, and may induce nitric oxide (NO) release from macrophages which probably protective against spondyloarthropaties as well. Considering premised possible influence of Hsp70s on core mechanisms of spondyloarthropaties it may be expected that, increased expression of Hsp70s advantageously retards disease progress, or may lead to remission. On the other hand Hsp70s as danger signals induces the secretion of proinflammatory cytokines playing major role in the progression of spondyloarthropaty induced bone loss. Consequently, the effect of Hsp70s on the progression of spondyloarthropathic bone loss is "Janus-faced" in some respect: increase of Hsp70s' level is likely advantageous regarding to the core of disorder; but it may facilitate existing bone resorption processes.

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Oncogenic KRAS signaling and YAP1/β-catenin: Similar cell cycle control in tumor initiation

Seminars in cell & developmental biology, Oct 4, 2016

Why are YAP1 and c-Myc often overexpressed (or activated) in KRAS-driven cancers and drug resista... more Why are YAP1 and c-Myc often overexpressed (or activated) in KRAS-driven cancers and drug resistance? Here, we propose that there are two independent pathways in tumor proliferation: one includes MAPK/ERK and PI3K/A kt/mTOR; and the other consists of pathways leading to the expression (or activation) of YAP1 and c-Myc. KRAS contributes through the first. MYC is regulated by e.g. β-catenin, Notch and Hedgehog. We propose that YAP1 and ERK accomplish similar roles in cell cycle control, as do β-catenin and PI3K. This point is compelling, since the question of how YAP1 rescues K-Ras or B-Raf ablation has recently captured much attention, as well as the mechanism of resistance to PI3K inhibitors. The similarity in cell cycle actions of β-catenin and PI3K can also clarify the increased aggressiveness of lung cancer when both K-Ras and β-catenin operate. Thus, we propose that the two pathways can substitute one another - or together amplify each other - in promoting proliferation. This ne...

SignaFish: A Zebrafish-Specific Signaling Pathway Resource

Zebrafish, Dec 20, 2016

Understanding living systems requires an in-depth knowledge of the signaling networks that drive ... more Understanding living systems requires an in-depth knowledge of the signaling networks that drive cellular homeostasis, regulate intercellular communication, and contribute to cell fates during development. Several resources exist to provide high-throughput data sets or manually curated interaction information from human or invertebrate model organisms. We previously developed SignaLink, a uniformly curated, multi-layered signaling resource containing information for human and for the model organisms nematode Caenorhabditis elegans and fruit fly Drosophila melanogaster. Until now, the use of the SignaLink database for zebrafish pathway analysis was limited. To overcome this limitation, we created SignaFish ( http://signafish.org ), a fish-specific signaling resource, built using the concept of SignaLink. SignaFish contains more than 200 curation-based signaling interactions, 132 further interactions listed in other resources, and it also lists potential miRNA-based regulatory connect...

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Zinc increases the affinity of phrobol ester receptor in T lymphocytes

Biochemical and Biophysical Research Communications, 1988

[The effect of heat stimulation and mechanical stress (massage) of salivary glands on the secretory parameters of salivary Hsp70. A pilot study]

Fogorvosi Szemle, Oct 1, 2004

The presence of Hsp70 in human whole saliva was demonstrated in the authors' previous study. In t... more The presence of Hsp70 in human whole saliva was demonstrated in the authors' previous study. In the recent study the authors investigated, whether repeated, short-term heat and mechanical stimulation of the salivary glands can specifically modify the salivary Hsp70 concentration in the human whole saliva. Some other basic secretory parameters, like salivary secretion rate, total protein concentration and amylase activity of the whole saliva were also measured. Both kind of stimulation increased the secretory rate significantly (p < or = 0.05), during stimulation, but it decreased to control level in resting phases. Hsp70 concentration increased after the first stimulation in the case of mechanical stress and after the second stimulation in the case of heat stimulation. In contrast, a significant (p < or = 0.05) confluent increase of total protein concentration and amylase activity occurred after the first stimulation in the case of heat stimulation and after the second stimulation in the case of mechanical stress. Further investigations are needed to evaluate the durability and clinical importance of salivary changes following local heat and massage stimulation.

壽Chaperones come of age

Cell Stress Chaperones, Apr 1, 2002

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Science education : best practices of research training for students under 21

Chemical chaperones: mechanisms of action and potential use

Handbook of experimental pharmacology, 2006

An increasing number of studies indicate that low-molecular-weight compounds can help correct con... more An increasing number of studies indicate that low-molecular-weight compounds can help correct conformational diseases by inhibiting the aggregation or enable the mutant proteins to escape the quality control systems, and thus their function can be rescued. The small molecules were named chemical chaperones and it is thought that they nonselectively stabilize the mutant proteins and facilitate their folding. Chemical chaperones are usually osmotically active, such as DMSO, glycerol, or deuterated water, but other compounds, such as 4-phenylbutiric acid, are also members of the chemical chaperone group. More recently, compounds such as receptor ligands or enzyme inhibitors, which selectively recognize the mutant proteins, were also found to rescue conformational mutants and were termed pharmacological chaperones. An increasing amount of evidence suggests that the action of pharmacological chaperones could be generalized to a large number of misfolded proteins, representing new therape...

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Water and cellular folding processes

Cellular and molecular biology (Noisy-le-Grand, France), 2001

Proteins require a unique, native structure to perform their functions. Water molecules play an i... more Proteins require a unique, native structure to perform their functions. Water molecules play an important role to develop and maintain this three-dimensional structure. Water is also necessary for several forms of enzyme catalysis, and is a constituent of many protein-protein, protein-DNA, or protein-RNA interfaces. Larger proteins acquire their native structure in a complicated folding pathway having several folding traps. Recent data indicated a key role of water molecules in this process. Protein flexibility, structural rearrangements, conformational transitions all require the fluctuating changes in hydrogen bond structure provided by interacting water molecules. Besides proteins, RNA and DNA structure is also heavily influenced by the presence of water. This review summarizes the important aspects of these fields, and draws attention to several open questions and hypotheses.

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