Genetic variant in the HSPB1 promoter region impairs the HSP27 stress response
| Autor: | Christine Van Broeckhoven, Joy Irobi, Robin Lemmens, Ellen Corsmit, Wim Robberecht, Jessie Theuns, Ines Dierick, Sophie Janssens, An Jacobs, Nicole Hersmus, Ludo Van Den Bosch, Vincent Timmerman, Peter De Jonghe |
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| Rok vydání: | 2007 |
| Předmět: |
Male
animal structures Transcription Genetic DNA Mutational Analysis Molecular Sequence Data HSP27 Heat-Shock Proteins Electrophoretic Mobility Shift Assay Response Elements Hsp27 Transcription (biology) Heat shock protein Chlorocebus aethiops Consensus Sequence Genetics Animals Humans Electrophoretic mobility shift assay Heat shock Allele HSF1 Promoter Regions Genetic Genetics (clinical) Heat-Shock Proteins biology Base Sequence Promoter Middle Aged Molecular biology Neoplasm Proteins COS Cells Mutation biology.protein Female Human medicine Heat-Shock Response Molecular Chaperones Protein Binding |
| Zdroj: | Human mutation |
| ISSN: | 1098-1004 1059-7794 |
| Popis: | The 27kDa heat shock protein 1 (HSP27) is a member of the ubiquitously expressed small heat shock protein family and has pleiotropic cytoprotective functions. Since HSP27 may act as a motor neuron survival factor, we analyzed the genetic contribution of the human HSPB1 gene (HSPB1) to the etiology of amyotrophic lateral sclerosis (ALS). In a cohort of sporadic ALS patients, we identified three rare genetic variations and one of which (c.-217T>C) targeted a conserved nucleotide of the Heat Shock Element (HSE) in the HSPB1 promoter. Since binding of Heat Shock Factor 1 (HSF1) to this HSE is essential for stressinduced transcription of HSPB1, we examined the effect of the c.-217C allele on transcriptional activity and HSF binding. The basal promoter activity of the HSPB1 c.-217C mutant allele decreased to 50% as compared to the wild-type promoter in neuronal and nonneuronal cells. Following heat shock, the HSE variant attenuated significantly the stressrelated increase in transcription. Electrophoretic mobility shift assays demonstrated a dramatically reduced HSF-binding to the c.-217C mutant allele as compared to the c.-217T wild-type allele. In conclusion, our study underscores the importance of the c.-217T nucleotide for HSF binding and heat inducibility of HSPB1. Therefore, our study suggests that the functional HSPB1 variant may represent a genetic modifier in the pathogenesis of motor neuron disease; however, it is necessary to confirm this HSPB1 variant in additional ALS patients. (C) 2007 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
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