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Control of Foxo1 gene expression by co-activator P300.

Wondisford AR, Xiong L, Chang E, Meng S, Meyers DJ, Li M, Cole PA, He L - J. Biol. Chem. (2013)

Bottom Line: In the fed state, elevated insulin phosphorylates FOXO1 via AKT, leading to its nuclear exclusion and degradation.Because cAMP-PKA regulates hepatic glucose production through cAMP-response element-binding protein co-activators, we depleted these co-activators using adenoviral shRNAs.In addition, inhibition of histone acetyltransferase activity of P300 significantly decreased hepatic Foxo1 mRNA and FOXO1 protein levels in fasted mice, as well as fasting blood glucose levels.

View Article: PubMed Central - PubMed

Affiliation: From the Division of Metabolism, Department of Pediatrics and.

ABSTRACT
FOXO1 is an important downstream mediator of the insulin signaling pathway. In the fed state, elevated insulin phosphorylates FOXO1 via AKT, leading to its nuclear exclusion and degradation. A reduction in nuclear FOXO1 levels then leads to suppression of hepatic glucose production. However, the mechanism leading to expression of Foxo1 gene in the fasted state is less clear. We found that Foxo1 mRNA and FOXO1 protein levels of Foxo1 were increased significantly in the liver of mice after 16 h of fasting. Furthermore, dibutyrl cAMP stimulated the expression of Foxo1 at both mRNA and protein level in hepatocytes. Because cAMP-PKA regulates hepatic glucose production through cAMP-response element-binding protein co-activators, we depleted these co-activators using adenoviral shRNAs. Interestingly, only depletion of co-activator P300 resulted in the decrease of Foxo1 mRNA and FOXO1 protein levels. In addition, inhibition of histone acetyltransferase activity of P300 significantly decreased hepatic Foxo1 mRNA and FOXO1 protein levels in fasted mice, as well as fasting blood glucose levels. By characterization of Foxo1 gene promoter, P300 regulates the Foxo1 gene expression through the binding to tandem cAMP-response element sites in the proximal promoter region of Foxo1 gene.

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Depletion of P300 decreased Foxo1 mRNA levels in the liver.Foxo1 mRNA levels in the liver of mice with adenoviral shRNAs mediated depletion of P300 (a) or CBP (b), and sacrificed after 16 h fasting (n = 3). Asterisk (*) signifies that groups with the same treatment are significantly different (p < 0.05). Error bars, S.D.
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Figure 4: Depletion of P300 decreased Foxo1 mRNA levels in the liver.Foxo1 mRNA levels in the liver of mice with adenoviral shRNAs mediated depletion of P300 (a) or CBP (b), and sacrificed after 16 h fasting (n = 3). Asterisk (*) signifies that groups with the same treatment are significantly different (p < 0.05). Error bars, S.D.

Mentions: Given the importance of CBP and P300 in regulation of gluconeogenic gene expression in the liver, we next assessed the role of CBP and P300 in regulation of Foxo1 gene expression in vivo. We used adenoviral shRNAs to deplete CBP or P300 in the liver of mice through tail vein injection. Depletion of P300 significantly decreased Foxo1 mRNA levels in the liver of fasted mice (Fig. 4a), whereas the depletion of CBP had a minimal effect on Foxo1 mRNA levels (Fig. 4b).


Control of Foxo1 gene expression by co-activator P300.

Wondisford AR, Xiong L, Chang E, Meng S, Meyers DJ, Li M, Cole PA, He L - J. Biol. Chem. (2013)

Depletion of P300 decreased Foxo1 mRNA levels in the liver.Foxo1 mRNA levels in the liver of mice with adenoviral shRNAs mediated depletion of P300 (a) or CBP (b), and sacrificed after 16 h fasting (n = 3). Asterisk (*) signifies that groups with the same treatment are significantly different (p < 0.05). Error bars, S.D.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3924295&req=5

Figure 4: Depletion of P300 decreased Foxo1 mRNA levels in the liver.Foxo1 mRNA levels in the liver of mice with adenoviral shRNAs mediated depletion of P300 (a) or CBP (b), and sacrificed after 16 h fasting (n = 3). Asterisk (*) signifies that groups with the same treatment are significantly different (p < 0.05). Error bars, S.D.
Mentions: Given the importance of CBP and P300 in regulation of gluconeogenic gene expression in the liver, we next assessed the role of CBP and P300 in regulation of Foxo1 gene expression in vivo. We used adenoviral shRNAs to deplete CBP or P300 in the liver of mice through tail vein injection. Depletion of P300 significantly decreased Foxo1 mRNA levels in the liver of fasted mice (Fig. 4a), whereas the depletion of CBP had a minimal effect on Foxo1 mRNA levels (Fig. 4b).

Bottom Line: In the fed state, elevated insulin phosphorylates FOXO1 via AKT, leading to its nuclear exclusion and degradation.Because cAMP-PKA regulates hepatic glucose production through cAMP-response element-binding protein co-activators, we depleted these co-activators using adenoviral shRNAs.In addition, inhibition of histone acetyltransferase activity of P300 significantly decreased hepatic Foxo1 mRNA and FOXO1 protein levels in fasted mice, as well as fasting blood glucose levels.

View Article: PubMed Central - PubMed

Affiliation: From the Division of Metabolism, Department of Pediatrics and.

ABSTRACT
FOXO1 is an important downstream mediator of the insulin signaling pathway. In the fed state, elevated insulin phosphorylates FOXO1 via AKT, leading to its nuclear exclusion and degradation. A reduction in nuclear FOXO1 levels then leads to suppression of hepatic glucose production. However, the mechanism leading to expression of Foxo1 gene in the fasted state is less clear. We found that Foxo1 mRNA and FOXO1 protein levels of Foxo1 were increased significantly in the liver of mice after 16 h of fasting. Furthermore, dibutyrl cAMP stimulated the expression of Foxo1 at both mRNA and protein level in hepatocytes. Because cAMP-PKA regulates hepatic glucose production through cAMP-response element-binding protein co-activators, we depleted these co-activators using adenoviral shRNAs. Interestingly, only depletion of co-activator P300 resulted in the decrease of Foxo1 mRNA and FOXO1 protein levels. In addition, inhibition of histone acetyltransferase activity of P300 significantly decreased hepatic Foxo1 mRNA and FOXO1 protein levels in fasted mice, as well as fasting blood glucose levels. By characterization of Foxo1 gene promoter, P300 regulates the Foxo1 gene expression through the binding to tandem cAMP-response element sites in the proximal promoter region of Foxo1 gene.

Show MeSH
Related in: MedlinePlus