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.
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Abstract
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.