Transcriptional repression of the c-fos gene by YY1 is mediated by a direct interaction with ATF/CREB.
Transcriptional activation of the mouse c-fos gene by the adenovirus 243-amino-acid E1A protein requires a binding site for transcription factor YY1 located at -54 of the c-fos promoter. YY1 normally represses transcription of c-fos, and this repression depends on the presence of a cyclic AMP (cAMP) response element located immediately upstream of the -54 YY1 DNA-binding site. This finding suggested that the mechanism of transcriptional repression by YY1 might involve a direct interaction with members of the ATF/CREB family of transcription factors. In vitro and in vivo binding assays were used to demonstrate that YY1 can interact with ATF/CREB proteins, including CREB, ATF-2, ATFa1, ATFa2, and ATFa3. Structure-function analyses of YY1 and ATFa2 revealed that the C-terminal zinc finger domain of YY1 is necessary and sufficient for binding to ATFa2 and that the basic-leucine zipper region of ATFa2 is necessary and sufficient for binding to YY1. Overexpression of YY1 in HeLa cells resulted in repression of a mutant c-fos chloramphenicol acetyltransferase reporter that lacked binding sites for YY1, suggesting that repression can be triggered through protein-protein interactions with ATF/CREB family members. Consistent with this finding, repression was relieved upon removal of the upstream cAMP response element. These data support a model in which YY1 binds simultaneously to its own DNA-binding site in the c-fos promoter and also to adjacent DNA-bound ATF/CREB proteins in order to effect repression. They further suggest that the ATF/CREB-YY1 complex serves as a target for the adenovirus 243-amino-acid E1A protein.
Zhou
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Department of Microbiology and Cancer Center, University of Virginia School of Medicine, Charlottesville 22908, USA.
Gedrich
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Engel
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DA
D051698:Activating Transcription Factor 2; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D050981:Erythroid-Specific DNA-Binding Factors; D051790:G-Box Binding Factors; D016762:Genes, fos; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000502:physiology*; D050986:YY1 Transcription Factor; D016335:Zinc Fingers
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D050976:Basic-Leucine Zipper Transcription Factors; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D051790:G-Box Binding Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D004247:DNA