Stress-induced transcription of the clusterin/apoJ gene

Michel, Denis; Chatelain, Gilles; North, Sophie; Brun, Gilbert

doi:10.1042/bj3280045

Cited by 191 publications

(141 citation statements)

References 49 publications

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“…Furthermore, recent studies of clusterin knock-out mice have suggested that clusterin protects mice from (i) the pathological consequences of inflammation associated with experimentally induced autoimmune myocarditis (4) and ischemia (5), although the latter claim has been disputed (6), and (ii) age-dependent deposition of antibody-containing aggregates in the kidney (7). The clusterin promoter contains a highly conserved 14-bp element, which is recognized by the transcriptional regulator heat shock factor 1 (8). Heat shock factor 1 activates expression of heat shock proteins (which protect cells from stresses) and clusterin (8).…”

mentioning

confidence: 99%

Mildly Acidic pH Activates the Extracellular Molecular Chaperone Clusterin

Poon¹,

Rybchyn

Easterbrook‐Smith

et al. 2002

Journal of Biological Chemistry

100

105

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Many features of the chaperone action of clusterin are similar to those of the intracellular small heat shock proteins (sHSPs) that, like clusterin, exist in solution as heterogeneous aggregates. Increased temperature induces dissociation of some sHSP aggregates and an enhanced chaperone action, suggesting that a dissociated form is the active chaperone species. We recently reported that clusterin aggregates dissociate at mildly acidic pH. To further explore the similarities between clusterin and the sHSPs, we tested the effects of temperature and pH on the structure of clusterin and its chaperone action. Our results demonstrate that increased temperature does not induce dissociation of clusterin aggregates, or other major structural changes, and has little effect on its chaperone action. However, we show that the chaperone action of clusterin is enhanced at mildly acidic pH. Clusterin is the first chaperone shown to be activated by reduced pH. This unique mode of activation appears to result from an increase in regions of solvent-exposed hydrophobicity, which is independent of any major changes in secondary or tertiary structure. We propose a model in which low pH-induced dissociation of clusterin aggregates increases the abundance of the heterodimeric chaperone-active species, which has greater hydrophobicity exposed to solution.

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mentioning

confidence: 99%

Mildly Acidic pH Activates the Extracellular Molecular Chaperone Clusterin

Poon¹,

Rybchyn

Easterbrook‐Smith

et al. 2002

Journal of Biological Chemistry

100

105

View full text Add to dashboard Cite

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“…The expression of clusterin is increased in a wide variety of models of stress and disease, including withdrawal of growth factors and exposure to noxious agents. 20 The transcriptional regulator heat shock factor 1 (HSF1) binds to a highly conserved 14 bp element in the clusterin promoter 21 and activates expression of both clusterin and heat shock proteins (which protect cells from stresses). 21 Clusterin is encoded by a single gene and the translated product is internally cleaved to produce its  and subunits, and glycosylated, prior to secretion from the cell.…”

Section: Clusterinmentioning

confidence: 99%

“…20 The transcriptional regulator heat shock factor 1 (HSF1) binds to a highly conserved 14 bp element in the clusterin promoter 21 and activates expression of both clusterin and heat shock proteins (which protect cells from stresses). 21 Clusterin is encoded by a single gene and the translated product is internally cleaved to produce its  and subunits, and glycosylated, prior to secretion from the cell. The exclusively N-linked glycosylation is variable in nature and extent, ranging from 17-27% (by weight).…”

Section: Clusterinmentioning

confidence: 99%

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity

2008

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The in vivo formation of fibrillar proteinaceous deposits called amyloid is associated with more than 40 serious human diseases, collectively referred to as protein deposition diseases. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is presented suggesting an important regulatory role for ECs in amyloid formation and disposal in the body. A model is presented which proposes that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific cell receptors for uptake and subsequent degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. Keywords: Extracellular chaperones, receptor-mediated endocytosis, amyloid, protein quality control, aggregate toxicity, fibril formation word statement (for Contents list) plus graphic (note -colour version of below graphic provided separately)Newly identified abundant extracellular chaperones (ECs) may protect the body against dangerously hydrophobic proteins/peptides. This review proposes that ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. SUMMARYThe in vivo formation of fibrillar proteinaceous deposits called amyloid is associated with more than 40 serious human diseases, collectively referred to as protein deposition diseases. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is presented suggesting an important regulatory role for ECs in amyloid formation and disposal in the body. A model is presented which proposes that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific cell receptors for uptake and subsequent degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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“…The clusterin promoter contains a highly conserved 14 bp element which is recognized by the transcriptional regulator heat shock factor 1 (HSF1) (Michel et al, 1997). HSF1 activates expression of heat shock proteins (which protect cells from stresses) and clusterin (Michel et al, 1997). Across different mammalian species, the amino acid sequence of the protein is maintained at the level of 70-80% (Jenne and Tschopp 1992).…”

Section: Clusterinmentioning

confidence: 99%

“…The expression of clusterin is increased in a wide variety of models of stress and disease, including withdrawal of growth factors and exposure to noxious agents (Jenne and Tschopp 1992). The clusterin promoter contains a highly conserved 14 bp element which is recognized by the transcriptional regulator heat shock factor 1 (HSF1) (Michel et al, 1997). HSF1 activates expression of heat shock proteins (which protect cells from stresses) and clusterin (Michel et al, 1997).…”

Section: Clusterinmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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Stress-induced transcription of the clusterin/apoJ gene

Cited by 191 publications

References 49 publications

Mildly Acidic pH Activates the Extracellular Molecular Chaperone Clusterin

Mildly Acidic pH Activates the Extracellular Molecular Chaperone Clusterin

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity

Extracellular Chaperones and Amyloids

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