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Induction of molecular chaperones is the characteristic protective response to environmental stress, and is regulated by a transcriptional program that depends on heat shock factor 1 (HSF1), which is normally under negative regulatory... more
Induction of molecular chaperones is the characteristic protective response to environmental stress, and is regulated by a transcriptional program that depends on heat shock factor 1 (HSF1), which is normally under negative regulatory control by molecular chaperones Hsp70 and Hsp90. In metazoan species, the chaperone system also provides protection against apoptosis. We demonstrate that the dual function co-chaperone/ubiquitin ligase CHIP (C-terminus of Hsp70-interacting protein) regulates activation of the stress-chaperone response through induced trimerization and transcriptional activation of HSF1, and is required for protection against stress-induced apoptosis in murine fibroblasts. The consequences of this function are demonstrated by the phenotype of mice lacking CHIP, which develop normally but are temperature-sensitive and develop apoptosis in multiple organs after environmental challenge. CHIP exerts a central and unique role in tuning the response to stress at multiple lev...
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Research Interests: Pharmacology, Biochemistry, Bioinformatics, Evolutionary Biology, Genetics, and 58 moreMarine Biology, Neuroscience, Environmental Science, Geophysics, Physics, Materials Science, Quantum Physics, Developmental Biology, Immunology, Climate Change, Molecular Biology, Structural Biology, Genomics, RNA, Protein Folding, Computational Biology, Transcriptomics, Biotechnology, Systems Biology, Cancer, Biology, Metabolomics, Cell Cycle, Proteomics, Ecology, Drug Discovery, Evolution, Transcription Regulation, Nanotechnology, Astrophysics, Transcription Factors, Neurobiology, Medicine, Gene expression, Multidisciplinary, Palaeobiology, Functional Genomics, Heat Shock Transcription Factor, Nature, Signal Transduction, Astronomy, DNA, Ubiquitin, Cell line, Humans, Mice, Animals, Cell Signalling, Medical Research, Chip, Ubiquitin Proteasome System, Ubiquitin ligase, Heat Shock Protein, Dual phase steels, Protein Binding, DNA binding proteins, Earth Science, and Acute stress
Research Interests: Stem Cells, Cell Cycle, Stem Cell, Apoptosis, Molecular, and 20 moreCell line, Cell Differentiation, Endothelial Cells, Mice, Animals, Chromatin remodeling, Histones, Zinc Finger, Lysine, Rats, Endothelial cell, Blood Vessels, Cell Proliferation, Amino Acid Sequence, Cell Survival, Full Length Movies, Gene Expression Regulation, Gene expression profiling, Vascular endothelial growth factor receptor, and Molecular Sequence Data
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Research Interests: Biological Chemistry, Apoptosis, Biological Sciences, Cell line, Humans, and 14 moreMice, Animals, Biological, Solubility, CHEMICAL SCIENCES, Cell nucleus, Chip, Lysine, Substrate Specificity, Physiological Stress Markers, Protein Binding, Protein Transport, Gene expression profiling, and Molecular Sequence Data
Research Interests: Protein Folding, Mass Spectrometry, Biological Chemistry, Quality Control, Biological Sciences, and 22 moreMolecular chaperones, Ubiquitin, Cell line, Humans, Biological, Chromatin, CHEMICAL SCIENCES, Time Factors, HeLa cells, Chromatin Immunoprecipitation, Protein Degradation, Transfection, Protein Conformation, Glutathione Transferase, Amino Acid Sequence, Protein Binding, Hydrogen-Ion Concentration, Cytoplasm, Gene Expression Regulation, Adenosine Triphosphate, Iron binding proteins, and Molecular Sequence Data
Research Interests: Adolescent, Biological Sciences, Cercopithecus aethiops, Humans, Cerebellum, and 13 moreMice, Female, Animals, Male, Human Molecular Genetics, Genetic Association Studies, Young Adult, Cerebellar ataxia, Phenotype, Late onset hypogonadism, Gonadotropin Releasing Hormone, Amino Acid Sequence, and Molecular Sequence Data
CHIP, carboxy terminus of Hsc70 interacting protein, is a cytoplasmic protein whose amino acid sequence is highly conserved across species. It is most highly expressed in cardiac and skeletal muscle and brain. The primary amino acid... more
CHIP, carboxy terminus of Hsc70 interacting protein, is a cytoplasmic protein whose amino acid sequence is highly conserved across species. It is most highly expressed in cardiac and skeletal muscle and brain. The primary amino acid sequence is characterized by 3 domains, a tetratricopeptide repeat (TPR) domain at its amino terminus, a U-box domain at its carboxy terminus, and an intervening charged domain. CHIP interacts with the molecular chaperones Hsc70-Hsp70 and Hsp90 through its TPR domain, whereas its U-box domain contains its E3 ubiquitin ligase activity. Its interaction with these molecular chaperones results in client substrate ubiquitylation and degradation by the proteasome. Thus, CHIP acts to tilt the folding-refolding machinery toward the degradative pathway, and it serves as a link between the two. Because protein degradation is required for healthy cellular function, CHIP's ability to degrade proteins that are the signature of disease, eg, ErbB2 in breast and ovarian cancers, could prove to be a point of therapeutic intervention.