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, ...
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...
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...
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...
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.
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.
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...
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.
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, ...
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...
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...
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...
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.
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.
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...
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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