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J. Biol. Chem., Vol. 275, Issue 30, 23387-23397, July 28, 2000
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§,
, and**
From the Fibroblast growth factor
(FGF)-4 gene expression in the inner cell mass of the
blastocyst and in EC cells requires the combined activity of two
transcriptional regulators, Sox2 and Oct-3, which bind to adjacent
sites on the FGF-4 enhancer DNA and synergistically activate transcription. Sox2 and Oct-3 bind cooperatively to the enhancer DNA through their DNA-binding, high mobility group and POU
domains, respectively. These two domains, however, are not sufficient
to activate transcription. We have analyzed a number of Sox2 and Oct-3
deletion mutants to identify the domains within each protein that
contribute to the activity of the Sox2·Oct-3 complex. Within Oct-3,
we have identified two activation domains, the N-terminal AD1 and the
C-terminal AD2, that play a role in the activity of the Sox2·Oct-3
complex. AD1 also displays transcriptional activation functions in the
absence of Sox2 while AD2 function was only detected within the
Sox2·Oct-3 complex. In Sox2, we have identified three activation
domains within its C terminus: R1, R2, and R3. R1 and R2 can potentiate
weak activation by Sox2 in the absence of Oct-3 but their deletion has
no effect on the Sox2·Oct-3 complex. In contrast, R3 function is only
observed when Sox2 is complexed with Oct-3. In addition, analysis of
Oct-1/Oct-3 chimeras indicates that the Oct-3 homeodomain also plays a
critical role in the formation of a functional Sox2·Oct-3 complex.
Our results are consistent with a model in which the synergistic action
of Sox2 and Oct-3 results from two major processes. Cooperative binding of the factors to the enhancer DNA, mediated by their binding domains,
stably tethers each factor to DNA and increases the activity of
intrinsic activation domains within each protein. Protein-protein and
protein-DNA interactions then may lead to reciprocal conformational changes that expose latent activation domains within each protein. These findings define a mechanism that may also be utilized by other Sox·POU protein complexes in gene activation.
Department of Microbiology, New York
University School of Medicine, New York, New York 10016 and the
¶ Center for Animal Transgenesis and Germ Cell Research, New
Bolton Center, University of Pennsylvania,
Kennett Square, Pennsylvania 19348
To whom correspondence may be addressed. Tel.: 212-263-0525;
Fax: 212-263-8714; E-mail: dailel01@med.nyu.edu.
**
To whom correspondence may be addressed. Tel.: 212-263-5341; Fax:
212-263-8714; E-mail: basilc01@med.nyu.edu.
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