Biomedical subjects

Csaba Soti

Publications and source records attributed to Csaba Soti.

8 recordsLinked to original sources

PubMed2006

Cellular networks and the aging process.

The most important interactions between cellular molecules have a high affinity, are unique and specific, and require a network approach for a detailed description. After a brief introduction to cellular networks (protein--protein interaction networks, metabolic networks, gene regulatory networks, signalling networks and membrane--organelle networks) an overview is given on the network aspects of the theories on aging. The most important part of the review summarizes our knowledge on the aging of networks. The effects of aging on the general network models are described, as well as the initial findings on the effects of aging on the cellular networks. Finally we suggest a 'weak link theory of aging' linking the random damage of the network constituents to the overwhelming majority of the low affinity, transient interactions (weak links) in the cellular networks. We show that random damage of weak links may lead to an increase of noise and an increased vulnerability of cellular networks, and make a comparison between these predictions and the observed behaviour of the emergent properties of cellular networks in aged organisms.

Aging↗

PubMed2005

Molecular chaperones as regulatory elements of cellular networks.

Molecular chaperones help hundreds of signaling molecules to keep their activation-competent state, and regulate various signaling processes ranging from signaling at the plasma membrane to transcription. Besides these specific regulatory roles, recent studies have revealed that chaperones act as genetic buffers stabilizing the phenotypes of various cells and organisms. This may be related to their low affinity for the proteins they interact with, which means that they represent weak links in protein networks. Chaperones may uncouple protein, signaling, membrane, organelle and transcriptional networks during stress, which gives the cell additional protection. The same networks are preferentially remodeled in various diseases and aging, which may help us to design novel therapeutic and anti-aging strategies.

Animals↗

PubMed2005

Modelling the actions of chaperones and their role in ageing.

Many molecular chaperones are also known as heat shock proteins because they are synthesised in increased amounts after brief exposure of cells to elevated temperatures. They have many cellular functions and are involved in the folding of nascent proteins, the re-folding of denatured proteins, the prevention of protein aggregation, and assisting the targeting of proteins for degradation by the proteasome and lysosomes. They also have a role in apoptosis and are involved in modulating signals for immune and inflammatory responses. Stress-induced transcription of heat shock proteins requires the activation of heat shock factor (HSF). Under normal conditions, HSF is bound to heat shock proteins resulting in feedback repression. During stress, cellular proteins undergo denaturation and sequester heat shock proteins bound to HSF, which is then able to become transcriptionally active. The induction of heat shock proteins is impaired with age and there is also a decline in chaperone function. Aberrant/damaged proteins accumulate with age and are implicated in several important age-related conditions (e.g. Alzheimer's disease, Parkinson's disease, and cataract). Therefore, the balance between damaged proteins and available free chaperones may be greatly disturbed during ageing. We have developed a mathematical model to describe the heat shock system. The aim of the model is two-fold: to explore the heat shock system and its implications in ageing; and to demonstrate how to build a model of a biological system using our simulation system (biology of ageing e-science integration and simulation (BASIS)).

Animals↗

PubMed2004

Inhibition of Hsp90: a new strategy for inhibiting protein kinases.

The 90-kDa heat shock protein (Hsp90) is a ubiquitous, evolutionarily highly conserved, molecular chaperone in the eukaryotic cytosol. Hsp90, together with a number of other chaperones, promotes the conformational maturation of a large variety of protein kinases. Inhibition of Hsp90 function results in the collapse of the metastable conformation of most of these kinases and leads to their proteolytic elimination by the proteasome. Numerous natural and synthetic Hsp90 inhibitors have been developed in recent years. Some of these inhibitors are also involved in sensitizing tumor cells to pro-apoptotic insults, hence serve as anti-cancer drugs. Here we review these novel protein kinase inhibitors and their emerging role in various cellular processes, apart from their inhibition of Hsp90 protein function. We focus not only on Hsp90-tumor progression, but also on cytoarchitecture, as the higher levels of cellular organization need constant remodeling, where the role of Hsp90 requires investigation. Our last major aspect deals with protein oxidation, since several Hsp90 inhibitors exert pro-oxidant effects.

Animals↗

PubMed2003

Aging and molecular chaperones.

Chaperone function plays a key role in sequestering damaged proteins and in repairing proteotoxic damage. Chaperones are induced by environmental stress and are called as stress or heat shock proteins. Here, we summarize the current knowledge about protein damage in aged organisms, about changes in proteolytic degradation, chaperone expression and function in the aging process, as well as the involvement of chaperones in longevity and cellular senescence. The role of chaperones in aging diseases, such as in Alzheimer's disease, Parkinson's disease, Huntington's disease and in other neurodegenerative diseases as well as in atherosclerosis and in cancer is discussed. We also describe how the balance between chaperone requirement and availability becomes disturbed in aged organisms, or in other words, how chaperone overload develops. The consequences of chaperone overload are also outlined together with several new research strategies to assess the functional status of chaperones in the aging process.

Aging↗

PubMed2003

Comparative analysis of the ATP-binding sites of Hsp90 by nucleotide affinity cleavage: a distinct nucleotide specificity of the C-terminal ATP-binding site.

The 90-kDa heat shock protein (Hsp90) is a molecular chaperone that assists both in ATP-independent sequestration of damaged proteins, and in ATP-dependent folding of numerous targets, such as nuclear hormone receptors and protein kinases. Recent work from our lab and others has established the existence of a second, C-terminal nucleotide binding site besides the well characterized N-terminal, geldanamycin-sensitive ATP-binding site. The cryptic C-terminal site becomes open only after the occupancy of the N-terminal site. Our present work demonstrates the applicability of the oxidative nucleotide affinity cleavage in the site-specific characterization of nucleotide binding proteins. We performed a systematic analysis of the nucleotide binding specificity of the Hsp90 nucleotide binding sites. N-terminal binding is specific to adenosine nucleotides with an intact adenine ring. Nicotinamide adenine dinucleotides and diadenosine polyphosphate alarmones are specific N-terminal nucleotides. The C-terminal binding site is much more unspecific-it interacts with both purine and pirimidine nucleotides. Efficient binding to the C-terminal site requires both charged residues and a larger hydrophobic moiety. GTP and UTP are specific C-terminal nucleotides. 2',3'-O-(2,4,6-trinitrophenyl)-nucleotides (TNP-ATP, TNP-GTP) and pyrophosphate access the C-terminal binding site without the need for an occupied N-terminal site. Our data provide additional evidence for the dynamic domain-domain interactions of Hsp90, give hints for the design of novel types of specific Hsp90 inhibitors, and raise the possibility that besides ATP, other small molecules might also interact with the C-terminal nucleotide binding site in vivo.

Adenosine Triphosphate↗

PubMed2002

Chaperones come of age.

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.

Aging↗

PubMedDate not supplied

Protein homeostasis and molecular chaperones in aging.

Molecular chaperones are ubiquitous, highly conserved proteins responsible for the maintenance of protein folding homeostasis in cells. Environmental stress causes proteotoxic damage, which triggers chaperone induction and the subsequent reparation of cellular damage by chaperones, including disposing irreparable protein ensembles. We summarize the current view of protein damage, turnover, the stress response and chaperone function in aging, and review novel data showing that accumulation of misfolded proteins outcompete and overload the limited resources of the protein folding, maintenance and turnover system, compromising general protein homeastasis and cellular function. Possible involvement of chaperones and proteolysis in immunosenescence is highlighted. Defects in zinc metabolism are also addressed in relation to aging and changes in chaperone levels.

Aging↗