Repression of Transcriptional Activity of C/EBPα by E2F-Dimerization Partner Complexes
Copyright policy )Repression of Transcriptional Activity of C/EBPα by E2F-Dimerization Partner Complexes
The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha) coordinates proliferation arrest and the differentiation of myeloid progenitors, adipocytes, hepatocytes, keratinocytes, and cells of the lung and placenta. C/EBPalpha transactivates lineage-specific differentiation genes and inhibits proliferation by repressing E2F-regulated genes. The myeloproliferative C/EBPalpha BRM2 mutant serves as a paradigm for recurrent human C-terminal bZIP C/EBPalpha mutations that are involved in acute myeloid leukemogenesis. BRM2 fails to repress E2F and to induce adipogenesis and granulopoiesis. The data presented here show that, independently of pocket proteins, C/EBPalpha interacts with the dimerization partner (DP) of E2F and that C/EBPalpha-E2F/DP interaction prevents both binding of C/EBPalpha to its cognate sites on DNA and transactivation of C/EBP target genes. The BRM2 mutant, in addition, exhibits enhanced interaction with E2F-DP and reduced affinity toward DNA and yet retains transactivation potential and differentiation competence that becomes exposed when E2F/DP levels are low. Our data suggest a tripartite balance between C/EBPalpha, E2F/DP, and pocket proteins in the control of proliferation, differentiation, and tumorigenesis.
- Charité - University Medicine Berlin Germany
- Humboldt-Universität zu Berlin Germany
Binding Sites, Molecular Sequence Data, Cell Differentiation, DNA, Models, Biological, Cell Line, E2F Transcription Factors, Repressor Proteins, Mice, Gene Knockdown Techniques, Consensus Sequence, Mutation, CCAAT-Enhancer-Binding Protein-alpha, Animals, Humans, Mutant Proteins, Amino Acid Sequence, Protein Multimerization, Promoter Regions, Genetic, Protein Binding
Binding Sites, Molecular Sequence Data, Cell Differentiation, DNA, Models, Biological, Cell Line, E2F Transcription Factors, Repressor Proteins, Mice, Gene Knockdown Techniques, Consensus Sequence, Mutation, CCAAT-Enhancer-Binding Protein-alpha, Animals, Humans, Mutant Proteins, Amino Acid Sequence, Protein Multimerization, Promoter Regions, Genetic, Protein Binding
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