Affiliation:
1. Department of Cell Biology, Harvard Medical School, 1 Boston, Massachusetts 02215, and
2. Howard Hughes Medical Institute, Salk Institute, La Jolla, California 920372
3. Joslin Diabetes Center 3 and
Abstract
ABSTRACT
Homeobox (
hox
) proteins have been shown to regulate cell fate and segment identity by promoting the expression of specific genetic programs. In contrast to their restricted biological action in vivo, however, most homeodomain factors exhibit promiscuous DNA binding properties in vitro, suggesting a requirement for additional cofactors that enhance target site selectivity. In this regard, the
pbx
family of homeobox genes has been found to heterodimerize with and thereby augment the DNA binding activity of certain
hox
proteins on a subset of potential target sites. Here we examine the transcriptional properties of a forced
hox-pbx
heterodimer containing the pancreas-specific orphan homeobox factor
pdx
fused to
pbx-1a
. Compared to the
pdx
monomer, the forced
pdx-pbx1a
dimer, displayed 10- to 20-fold-higher affinity for a consensus
hox-pbx
binding site but was completely unable to bind a
hox
monomer recognition site. The
pdx-pbx
dimer stimulated target gene expression via an N-terminal
trans
-activation domain in
pdx
that interacts with the coactivator CREB binding protein. The
pdx-pbx
dimer was also found to repress transcription via a C-terminal domain in
pbx-1a
that associates with the corepressors SMRT and NCoR. The transcriptional properties of the
pdx-pbx1
complex appear to be regulated at the level of alternative splicing; a
pdx-pbx
polypeptide containing the
pbx1b
isoform, which lacks the C-terminal extension in
pbx1a
, was unable to repress target gene expression via NCoR-SMRT. Since
pbx1a
and
pbx1b
are differentially expressed in endocrine versus exocrine compartments of the adult pancreas, our results illustrate a novel mechanism by which
pbx
proteins may modulate the expression of specific genetic programs, either positively or negatively, during development.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
112 articles.
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