Mammalian Gene Expression Program Resiliency: The Roles of Multiple Coactivator Mechanisms in Hypoxia–Responsive Transcription
Volume 5, Issue 2
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January 16, 2006
Pages 142 - 146http://dx.doi.org/10.4161/cc.5.2.2353
Authors: Lawryn H. Kasper and Paul K. Brindle View affiliations
Abstract. CBP and its paralog p300 (CBP/p300 collectively) are transcriptional
coactivators that are among the most interconnected proteins in the mammalian proteinprotein
“interactome”, with over 315 described interaction partners. CBP/p300 are
protein/histone acetyltransferases, but most of the protein-binding domains of
CBP/p300 are unique to these two coactivators, indicating that CBP/p300 should be
highly limiting. The CH1 domain of CBP/p300 was considered essential for most, if not
all, hypoxia-inducible transcription by binding to hypoxia-inducible-factor-1? (HIF-1?).
Mutating CH1 had little effect, however, on the hypoxia-induced transcription of the HIFtarget
genes Higd1a, Egln1 (prolyl-hydroxylase), Bnip3 (Bcl2-interacting-protein-3), and
Pfkl (phosphofructokinase). In contrast, HIF-targets Pgf (placental growth factor) and
Egln3 were strongly affected by the CH1 mutation, while Stc1 (stanniocalcin-1) and
Slc2a1 (glucose-transporter-1) were moderately affected. HIF targets were also
dependent on coactivation mechanisms that are sensitive to trichostatin A (TSAS).
Paradoxically, TSA inhibits histone deacetylases (HDACs) that are usually associated
with transcriptional repression, implying that HDACs can also function as coactivators.
Thus, activator-specific transcription in mammals requires seemingly unrelated
coactivator mechanisms, and individual target genes vary in their requirements for each
mechanism. Gene expression program resiliency is therefore coupled with gene specific
regulation by avoiding uniform reliance on a “keystone” coactivator interaction.