title: CCAAT/Enhancer-binding protein beta DNA binding is auto-inhibited by multiple elements that also mediate association with p300/CREB-binding protein (CBP).
abstract: Signaling through Ras GTPases controls the activity of many transcription factors including CCAAT/enhancer-binding protein (C/EBPbeta), which regulates oncogenic H-Ras(V12)-induced senescence and growth arrest. Here we report that C/EBPbeta (LAP) DNA binding is inhibited by N-terminal sequences and derepressed by oncogenic Ras signaling. Sequence and mutational analyses showed that auto-repression involves two LXXLF (phiXXphiphi)-like motifs (LX1 and LX2) and a third element, auto-inhibitory domain (AID), located within conserved region CR5. LX1 is a critical component of the transactivation domain and has been shown to mediate C/EBPbeta binding to the TAZ2 region of p300/CREB-binding protein coactivators. C/EBPbeta auto-repression also involves a C-terminal regulatory domain (CRD) adjacent to the leucine zipper. CRD contains a third phiXXphiphi motif (LX3) and a short sequence, KQL, which has similarity to a region in the protein-binding site of TAZ2. The C/EBPbeta N- and C-terminal domains physically associate in a manner that requires the basic region and CRD. We propose a model in which the regulatory sequences form a hydrophobic core that reciprocally inhibits DNA binding and transactivation. We also suggest a mechanism for C/EBPbeta derepression involving several recently identified modifications within AID and CRD. Finally, we show that association of activated C/EBPbeta with p300/CREB-binding protein requires the LX2 and AID auto-inhibitory elements. Thus, the N-terminal regulatory elements have dual roles in auto-inhibition and coactivator binding.
authors.affiliation: Laboratory of Cancer Prevention, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702-1201, USA.
authors.forename: Sook
authors.initials: S
authors.lastname: Lee
authors.forename: Maria
authors.initials: M
authors.lastname: Miller
authors.forename: Jon D
authors.initials: JD
authors.lastname: Shuman
authors.forename: Peter F
authors.initials: PF
authors.lastname: Johnson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D004247:DNA / Q000737:chemistry*; D004742:Enhancer Elements, Genetic; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D004247:DNA; D050880:p300-CBP Transcription Factors
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