title: The mammalian HSF4 gene generates both an activator and a repressor of heat shock genes by alternative splicing.
abstract: The expression of heat shock genes is controlled at the level of transcription by members of the heat shock transcription factor family in vertebrates. HSF4 is a mammalian factor characterized by its lack of a suppression domain that modulates formation of DNA-binding homotrimer. Here, we have determined the exon structure of the human HSF4 gene and identified a major new isoform, HSF4b, derived by alternative RNA splicing events, in addition to a previously reported HSF4a isoform. In mouse tissues HSF4b mRNA was more abundant than HSF4a as examined by reverse transcription-polymerase chain reaction, and its protein was detected in the brain and lung. Although both mouse HSF4a and HSF4b form trimers in the absence of stress, these two isoforms exhibit different transcriptional activity; HSF4a acts as an inhibitor of the constitutive expression of heat shock genes, and hHSF4b acts as a transcriptional activator. Furthermore HSF4b but not HSF4a complements the viability defect of yeast cells lacking HSF. Moreover, heat shock and other stresses stimulate transcription of target genes by HSF4b in both yeast and mammalian cells. These results suggest that differential splicing of HSF4 mRNA gives rise to both an inhibitor and activator of tissue-specific heat shock gene expression.
authors.affiliation: Department of Molecular and Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8397, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanabe
authors.forename: N
authors.initials: N
authors.lastname: Sasai
authors.forename: K
authors.initials: K
authors.lastname: Nagata
authors.forename: X D
authors.initials: XD
authors.lastname: Liu
authors.forename: P C
authors.initials: PC
authors.lastname: Liu
authors.forename: D J
authors.initials: DJ
authors.lastname: Thiele
authors.forename: A
authors.initials: A
authors.lastname: Nakai
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005786:Gene Expression Regulation; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014714:Vertebrates
chemical_list: D004268:DNA-Binding Proteins; C102948:HSF4 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C484462:Hsf4 protein, mouse; D020033:Protein Isoforms; D011994:Recombinant Proteins; D014157:Transcription Factors