Molecular and Cellular Biology, March 1999, p. 1695-1704, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Regulates Generation of C/EBP
Isoforms
through Activation of Specific Proteolytic Cleavage
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030
Received 30 July 1998/Returned for modification 14 October 1998/Accepted 18 November 1998
C/EBP
and C/EBP
are intronless genes that can produce several
N-terminally truncated isoforms through the process of alternative translation initiation at downstream AUG codons. C/EBP
has been reported to produce four isoforms: full-length 38-kDa C/EBP
, 35-kDa
LAP (liver-enriched transcriptional activator protein), 21-kDa LIP
(liver-enriched transcriptional inhibitory protein), and a 14-kDa
isoform. In this report, we investigated the mechanisms by which
C/EBP
isoforms are generated in the liver and in cultured cells.
Using an in vitro translation system, we found that LIP can be
generated by two mechanisms: alternative translation and a novel
mechanism
specific proteolytic cleavage of full-length C/EBP
.
Studies of mice in which the C/EBP
gene had been deleted (C/EBP
/
) showed that the regulation of C/EBP
proteolysis is dependent on C/EBP
. The induction of C/EBP
in
cultured cells leads to induced cleavage of C/EBP
to generate the
LIP isoform. We characterized the cleavage activity in mouse liver
extracts and found that the proteolytic cleavage activity is specific
to prenatal and newborn livers, is sensitive to chymostatin, and is
completely abolished in C/EBP
/
animals. The lack of
cleavage activity in the livers of C/EBP
/
mice
correlates with the decreased levels of LIP in the livers of these
animals. Analysis of LIP production during liver regeneration showed
that, in this system, the transient induction of LIP is dependent on
the third AUG codon and most likely involves translational control. We
propose that there are two mechanisms by which C/EBP
isoforms might
be generated in the liver and in cultured cells: one that is determined
by translation and a second that involves C/EBP
-dependent, specific
proteolytic cleavage of full-length C/EBP
. The latter mechanism
implicates C/EBP
in the regulation of posttranslational generation
of the dominant negative C/EBP
isoform, LIP.
This article has been cited by other articles:
| J. Bacteriol. | J. Virol. | Eukaryot. Cell |
|---|
| Microbiol. Mol. Biol. Rev. | Clin. Vaccine Immunol. | All ASM Journals |
|---|