DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells
Open Access
- 5 September 2000
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 97 (19) , 10412-10417
- https://doi.org/10.1073/pnas.190326997
Abstract
Insulin negatively regulates expression of the insulin-like growth factor binding protein 1 (IGFBP-1) gene by means of an insulin-responsive element (IRE) that also contributes to glucocorticoid stimulation of this gene. We find that the Caenorhabditis elegans protein DAF-16 binds the IGFBP-1⋅IRE with specificity similar to that of the forkhead (FKH) factor(s) that act both to enhance glucocorticoid responsiveness and to mediate the negative effect of insulin at this site. In HepG2 cells, DAF-16 and its mammalian homologs, FKHR, FKHRL1, and AFX, activate transcription through the IGFBP-1⋅IRE; this effect is inhibited by the viral oncoprotein E1A, but not by mutants of E1A that fail to interact with the coactivator p300/CREB-binding protein (CBP). We show that DAF-16 and FKHR can interact with both the KIX and E1A/SRC interaction domains of p300/CBP, as well as the steroid receptor coactivator (SRC). A C-terminal deletion mutant of DAF-16 that is nonfunctional in C. elegans fails to bind the KIX domain of CBP, fails to activate transcription through the IGFBP-1⋅IRE, and inhibits activation of the IGFBP-1 promoter by glucocorticoids. Thus, the interaction of DAF-16 homologs with the KIX domain of CBP is essential to basal and glucocorticoid-stimulated transactivation. Although AFX interacts with the KIX domain of CBP, it does not interact with SRC and does not respond to glucocorticoids or insulin. Thus, we conclude that DAF-16 and FKHR act as accessory factors to the glucocorticoid response, by recruiting the p300/CBP/SRC coactivator complex to an FKH factor site in the IGFBP-1 promoter, which allows the cell to integrate the effects of glucocorticoids and insulin on genes that carry this site.Keywords
This publication has 53 references indexed in Scilit:
- The Phosphoenolpyruvate Carboxykinase Gene Glucocorticoid Response Unit: Identification of the Functional Domains of Accessory Factors HNF3 (Hepatic Nuclear Factor-3 ) and HNF4 and the Necessity of Proper Alignment of Their Cognate Binding SitesMolecular Endocrinology, 1999
- Structure and specificity of nuclear receptor–coactivator interactionsGenes & Development, 1998
- Two Separate NCoR (Nuclear Receptor Corepressor) Interaction Domains Mediate Corepressor Action on Thyroid Hormone Response ElementsMolecular Endocrinology, 1998
- IRE-ABP (Insulin Response Element-A Binding Protein), an SRY-Like Protein, Inhibits C/EBP (CCAAT/Enhancer-Binding Protein )-Stimulated Expression of the Sex-Specific Cytochrome P450 2C12 GeneMolecular Endocrinology, 1998
- daf-16 : An HNF-3/forkhead Family Member That Can Function to Double the Life-Span of Caenorhabditis elegansScience, 1997
- Hepatic Nuclear Factor 3 and High Mobility Group I/Y Proteins Bind the Insulin Response Element of the Insulin-Like Growth Factor-Binding Protein-1 PromoterEndocrinology, 1997
- Molecular cloning and properties of a full-length putative thyroid hormone receptor coactivatorEndocrinology, 1996
- Hepatic nuclear factor 3 is an accessory factor required for the stimulation of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoidsMolecular Endocrinology, 1996
- Hepatocyte Nuclear Factor-3 (HNF-3) Binds to the Insulin Response Sequence in the IGF Binding Protein-1 (IGFBP-1) Promoter and Enhances Promoter FunctionBiochemical and Biophysical Research Communications, 1994
- Identification of cis-elements mediating the stimulation of rat insulin- like growth factor-binding protein-1 promoter activity by dexamethasone, cyclic adenosine 3',5'-monophosphate, and phorbol esters, and inhibition by insulinMolecular Endocrinology, 1994