CREB binding protein coordinates the function of multiple transcription factors including nuclear factor I to regulate phosphoenolpyruvate carboxykinase (GTP) gene transcription
P. Leahy et al., CREB binding protein coordinates the function of multiple transcription factors including nuclear factor I to regulate phosphoenolpyruvate carboxykinase (GTP) gene transcription, J BIOL CHEM, 274(13), 1999, pp. 8813-8822
Nuclear factor I (NFI) binds to a region of the phosphoenolpyruvate carboxy
kinase (GTP) (PEPCK) gene promoter adjacent to the cAMP regulatory element
(CRE) and inhibits the induction of transcription from the gene promoter ca
used by the catalytic subunit of protein kinase A. In vivo footprinting stu
dies demonstrated that both the CRE and the NFI-binding site are occupied b
y transcription factors, regardless of the presence of factors that stimula
te (dibutyryl cAMP or dexamethasone) or inhibit (insulin) transcription fro
m the PEPCK gene promoter. The NFI effects on transcription from the PEPCK
gene promoter were observed even in the absence of the NFI binding site, su
ggesting the possibility of other weaker binding sites on the promoter or a
n interaction of NFI with a transcriptional co-activator. A mammalian two-h
ybrid system was used to demonstrate direct interaction between the transac
tivation domain of NFI-C and the CREB binding domain of the CREB-binding pr
otein (CBP), Overexpression of a gene fragment encoding the CREB binding do
main of CBP stimulates transcription from the PEPCK gene promoter. The inhi
bitory effect of NFI on transcription of the PEPCK gene induced by the cata
lytic subunit of protein kinase A appears to be the result of an interactio
n between NFI and the CREB-binding protein in which NFI competes with CREB
for binding to the CREB-binding site on CBP, In contrast, glucocorticoids a
nd thyroid hormone use the steroid hormone receptor binding domain of CBP t
o stimulate transcription from the PEPCK gene promoter. NFI-A combines with
dexamethasone or thyroid hormone in an additive manner to stimulate PEPCK
gene transcription. We conclude that CBP coordinates the action of the mult
iple factors known to control transcription of the PEPCK gene.