Molecular chaperones and the stress of oncogenesis.
TL;DR: It has been established that heat-shock proteins exhibit specificity to particular classes of polypeptide substrates and client proteins in vivo, and that chaperones can stabilize mutations that affect the folded conformation.
Abstract: Protein-damaging stresses induce the expression of 'heat-shock proteins', which have essential roles in protecting cells from the potentially lethal effects of stress and proteotoxicity. These stress-protective heat-shock proteins are often overexpressed in cells of various cancers and have been suggested to be contributing factors in tumorigenesis. An underlying basis of oncogenesis is the acquisition and accumulation of mutations that provide the transformed cell with the combined characteristics of deregulated cell proliferation and suppressed cell death. Heat-shock proteins with dual roles as regulators of protein conformation and stress sensors may therefore have intriguing and central roles in both cell proliferation and apoptosis. It has been established that heat-shock proteins exhibit specificity to particular classes of polypeptide substrates and client proteins in vivo, and that chaperones can stabilize mutations that affect the folded conformation. Likewise, overexpression of chaperones has also been shown to protect cells against apoptotic cell death. The involvement of chaperones, therefore, in such diverse roles might suggest novel anticancer therapeutic approaches targeting heat-shock protein function for a broad spectrum of tumor types.
Citations
More filters
TL;DR: Pharmacologically 'bribing' the essential guard duty of the chaperone HSP90 (heat-shock protein of 90 kDa) seems to offer a unique anticancer strategy of considerable promise.
Abstract: Standing watch over the proteome, molecular chaperones are an ancient and evolutionarily conserved class of proteins that guide the normal folding, intracellular disposition and proteolytic turnover of many of the key regulators of cell growth, differentiation and survival. This essential guardian function is subverted during oncogenesis to allow malignant transformation and to facilitate rapid somatic evolution. Pharmacologically 'bribing' the essential guard duty of the chaperone HSP90 (heat-shock protein of 90 kDa) seems to offer a unique anticancer strategy of considerable promise.
2,273 citations
TL;DR: This review summarizes the present knowledge of the individual members of human Hsp70 family and elaborate on the functional differences between the cytosolic/nuclear representatives.
1,055 citations
Cites background from "Molecular chaperones and the stress..."
...malignant tumors of various origins (reviewed in [15,101]), and its expression correlates with increased cell proliferation, poor differentiation, lymph node metastases and poor therapeutic outcome in human breast cancer [102–105]....
[...]
TL;DR: It is proposed that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades.
Abstract: Many neurodegenerative disorders are characterized by conformational changes in proteins that result in misfolding, aggregation and intra- or extra-neuronal accumulation of amyloid fibrils. Molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are among the most potent suppressors of neurodegeneration known for animal models of human disease. Recent studies have investigated the role of molecular chaperones in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and polyglutamine diseases. We propose that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades. A detailed understanding of the molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapies for neurodegenerative disorders that are associated with protein misfolding and aggregation.
1,020 citations
TL;DR: Challenges Eun-Kyung Lim,†,‡,§ Taekhoon Kim, Soonmyung Paik, Seungjoo Haam, Yong-Min Huh,*,† and Kwangyeol Lee
Abstract: Challenges Eun-Kyung Lim,†,‡,§ Taekhoon Kim, Soonmyung Paik, Seungjoo Haam, Yong-Min Huh,*,† and Kwangyeol Lee* Department of Chemistry, Korea University, Seoul 136-701, Korea †Department of Radiology, Yonsei University, Seoul 120-752, Korea Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul 120-749, Korea Division of Pathology, NSABP Foundation, Pittsburgh, Pennsylvania 15212, United States Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul 120-749, Korea ‡BioNanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea Electronic Materials Laboratory, Samsung Advanced Institute of Technology, Mt. 14-1, Nongseo-Ri, Giheung-Eup, Yongin-Si, Gyeonggi-Do 449-712, Korea
998 citations
Journal Article•
[...]
TL;DR: Investigations compel the view that the ratio of the vital capacity to the body length, trunk length, chest circumference, surface area or weight or any combination of these measurements, is too variable to admit of any workable standard or normal value.
Abstract: These investigations and several others that have beenpublishedwithin recentyears compel us us to hold the view that the ratio of the vital capacity to the body length, trunk length, chest circumference,surfacearea or weight or any combination of thesemeasurements, is too variable to admit of any workable standardor normal value. On the other hand the vital capacity of each individual, after he had becomeaccustomedto the use of the spirometer,will be found to be subjectto but small variations as long as good health is maintained. Thereseems to beevidenceto show that a reductionin the vital capacityis ofen the first sign of a progressivedamageto the respiratorytissue.
986 citations
References
More filters
TL;DR: Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) that control a vast array of physiological processes, and inhibitors of these enzymes are being explored as anticancer agents.
Abstract: Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) that control a vast array of physiological processes. These enzymes are regulated by a characteristic phosphorelay system in which a series of three protein kinases phosphorylate and activate one another. The extracellular signal-regulated kinases (ERKs) function in the control of cell division, and inhibitors of these enzymes are being explored as anticancer agents. The c-Jun amino-terminal kinases (JNKs) are critical regulators of transcription, and JNK inhibitors may be effective in control of rheumatoid arthritis. The p38 MAPKs are activated by inflammatory cytokines and environmental stresses and may contribute to diseases like asthma and autoimmunity.
3,999 citations
"Molecular chaperones and the stress..." refers background in this paper
...…variety of cellular stresses, including heat shock, oxidative stress, and UV exposure activate kinase signaling cascades wherein MAP3 kinases phosphorylate the MAP2 kinases MKK4/7 and MKK3/6, which in turn phosphorylate the MAP1 kinases JNK and p38 (reviewed in Johnson and Lapadat, 2002)....
[...]
TL;DR: Understanding how the thousands of different proteins synthesized in a cell use this chaperone machinery has profound implications for biotechnology and medicine.
Abstract: Efficient folding of many newly synthesized proteins depends on assistance from molecular chaperones, which serve to prevent protein misfolding and aggregation in the crowded environment of the cell. Nascent chain–binding chaperones, including trigger factor, Hsp70, and prefoldin, stabilize elongating chains on ribosomes in a nonaggregated state. Folding in the cytosol is achieved either on controlled chain release from these factors or after transfer of newly synthesized proteins to downstream chaperones, such as the chaperonins. These are large, cylindrical complexes that provide a central compartment for a single protein chain to fold unimpaired by aggregation. Understanding how the thousands of different proteins synthesized in a cell use this chaperone machinery has profound implications for biotechnology and medicine.
3,288 citations
"Molecular chaperones and the stress..." refers background in this paper
...…by interactions with co-chaperones Hsp70 influences the productive folding of proteins to the native state, and thus prevents protein misfolding and aggregation by binding to exposed stretches of hydrophobic amino acids in the substrate or client protein (reviewed in Hartl and Hayer-Hartl, 2002)....
[...]
TL;DR: It is reported that when Drosophila Hsp90 is mutant or pharmacologically impaired, phenotypic variation affecting nearly any adult structure is produced, with specific variants depending on the genetic background and occurring both in laboratory strains and in wild populations.
Abstract: The heat-shock protein Hsp90 supports diverse but specific signal transducers and lies at the interface of several developmental pathways. We report here that when Drosophila Hsp90 is mutant or pharmacologically impaired, phenotypic variation affecting nearly any adult structure is produced, with specific variants depending on the genetic background and occurring both in laboratory strains and in wild populations. Multiple, previously silent, genetic determinants produced these variants and, when enriched by selection, they rapidly became independent of the Hsp90 mutation. Therefore, widespread variation affecting morphogenic pathways exists in nature, but is usually silent; Hsp90 buffers this variation, allowing it to accumulate under neutral conditions. When Hsp90 buffering is compromised, for example by temperature, cryptic variants are expressed and selection can lead to the continued expression of these traits, even when Hsp90 function is restored. This provides a plausible mechanism for promoting evolutionary change in otherwise entrenched developmental processes.
2,160 citations
"Molecular chaperones and the stress..." refers background in this paper
...Similar to the role postulated for Hsp90 in buffering phenotypic variation in the environment (Rutherford and Lindquist, 1998), heat-shock proteins may buffer the potentially life-threatening effects of the numerous mutant proteins that arise due to the genetic instability of tumor cells....
[...]
TL;DR: It is reported that ceramide initiates apoptosis through the SAPK cascade and evidence is provided for a signalling mechanism that integrates cytokine- and stress-activated apoptosis.
Abstract: The induction of programmed cell death, or apoptosis, involves activation of a signalling system, many elements of which remain unknown. The sphingomyelin pathway, initiated by hydrolysis of the phospholipid sphingomyelin in the cell membrane to generate the second messenger ceramide, is thought to mediate apoptosis in response to tumour-necrosis factor (TNF)-alpha, to Fas ligand and to X-rays. It is not known whether it plays a role in the stimulation of other forms of stress-induced apoptosis. Given that environmental stresses also stimulate a stress-activated protein kinase (SAPK/JNK), the sphingomyelin and SAPK/JNK signalling systems may be coordinated in induction of apoptosis. Here we report that ceramide initiates apoptosis through the SAPK cascade and provide evidence for a signalling mechanism that integrates cytokine- and stress-activated apoptosis.
1,813 citations
TL;DR: It is shown here that JNK is required for UV-induced apoptosis in primary murine embryonic fibroblasts, and data indicate that mitochondria are influenced by proapoptotic signal transduction through the JNK pathway.
Abstract: The c-Jun NH2-terminal kinase (JNK) is activated when cells are exposed to ultraviolet (UV) radiation. However, the functional consequence of JNK activation in UV-irradiated cells has not been established. It is shown here that JNK is required for UV-induced apoptosis in primary murine embryonic fibroblasts. Fibroblasts with simultaneous targeted disruptions of all the functional Jnk genes were protected against UV-stimulated apoptosis. The absence of JNK caused a defect in the mitochondrial death signaling pathway, including the failure to release cytochrome c. These data indicate that mitochondria are influenced by proapoptotic signal transduction through the JNK pathway.
1,738 citations
"Molecular chaperones and the stress..." refers background in this paper
...Mouse embryo fibroblasts with targeted disruption of JNK1 and JNK2 were found to be resistant to UVinduced apoptosis due to their failure to release cytochrome c (Tournier et al., 2000)....
[...]