CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription.
We report on the identification of a nuclear protein that serves as a dominant-negative inhibitor of the transcription factors C/EBP and LAP. A 32P-labeled LAP DNA-binding and dimerization domain "zipper probe" was used to isolate a clone that encodes a new C/EBP-homologous protein: CHOP-10. CHOP-10 has strong sequence similarity to ... C/EBP-like proteins within the bZIP region corresponding to the DNA-binding domain consisting of a leucine zipper and a basic region. Notably, however, CHOP-10 contains 2 prolines substituting for 2 residues in the basic region, critical for binding to DNA. Thus, heterodimers of CHOP-10 and C/EBP-like proteins are unable to bind their cognate DNA enhancer element. CHOP-10 mRNA is expressed in many different rat tissues. Antisera raised against CHOP-10 recognize a nuclear protein with an apparent molecular mass of 29 kD. CHOP-10 is induced upon differentiation of 3T3-L1 fibroblasts to adipocytes, and cytokine-induced dedifferentiation of adipocytes is preceded by the loss of nuclear CHOP-10. Coimmunoprecipitation of CHOP-10 and LAP from transfected COS-1 cells demonstrated a direct interaction between the two proteins, in vivo. Consistent with the structure of its defective basic region, bacterially expressed CHOP-10 inhibits the DNA-binding activity of C/EBP and LAP by forming heterodimers that cannot bind DNA. In transfected HepG2 cells, expression of CHOP-10 attenuates activation of C/EBP- and LAP-driven promoters. We suggest that CHOP-10 is a negative modulator of the activity of C/EBP-like proteins in certain terminally differentiated cells, similar to the regulatory function of Id on the activity of MyoD and MyoD-related proteins important in the development of muscle cells.
Mesh Terms:
3T3 Cells, Amino Acid Sequence, Animals, Base Sequence, Blotting, Western, CCAAT-Enhancer-Binding Proteins, Cell Division, DNA, DNA-Binding Proteins, Immunohistochemistry, Leucine Zippers, Mice, Molecular Sequence Data, Nuclear Proteins, Plasmids, Precipitin Tests, RNA, Messenger, Sequence Alignment, Transcription Factor CHOP, Transcription Factors, Transcription, Genetic, Transfection
3T3 Cells, Amino Acid Sequence, Animals, Base Sequence, Blotting, Western, CCAAT-Enhancer-Binding Proteins, Cell Division, DNA, DNA-Binding Proteins, Immunohistochemistry, Leucine Zippers, Mice, Molecular Sequence Data, Nuclear Proteins, Plasmids, Precipitin Tests, RNA, Messenger, Sequence Alignment, Transcription Factor CHOP, Transcription Factors, Transcription, Genetic, Transfection
Genes Dev.
Date: Mar. 01, 1992
PubMed ID: 1547942
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