RGD Reference Report - Bidirectional regulation of upstream IGF-I/insulin receptor signaling and downstream FOXO1 in cardiomyocytes. - Rat Genome Database

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Bidirectional regulation of upstream IGF-I/insulin receptor signaling and downstream FOXO1 in cardiomyocytes.

Authors: Liu, TJ  Lai, HC  Ting, CT  Wang, PH 
Citation: Liu TJ, etal., J Endocrinol. 2007 Jan;192(1):149-58.
RGD ID: 2307037
Pubmed: PMID:17210752   (View Abstract at PubMed)
DOI: DOI:10.1677/joe.1.07020   (Journal Full-text)

Signaling pathways of IGF-I and insulin receptors play important roles in the regulation of myocardial function. FOXO1 is a member of the forkhead transcriptional factor family, but how insulin and IGF-I receptor signaling regulate FOXO1 in cardiomyocytes is not well understood. This study was carried out to elucidate how IGF-I and insulin receptor signaling modulate FOXO1 in cardiomyocytes. In cardiomyocytes, activation of IGF-I receptor and insulin receptor lead to rapid phosphorylation of FOXO1. Inhibition of phosphatidylinositol 3-kinase/Akt pathway suppressed the effect of insulin and IGF-I on FOXO1 phosphorylation. Prolonged incubation with IGF-I increased ubiquitination of FOXO1 and down-regulated the abundance of FOXO1 proteins, which suggested that IGF-I might modulate FOXO1 degradation. To explore whether FOXO1 could modulate IGF-I and insulin signaling, a constitutively active FOXO1 was overexpressed in cardiomyocytes. The abundance of insulin receptor and IGF-I receptor was significantly upregulated in the cells overexpressing active FOXO1, accompanied by increased receptor phosphorylation upon insulin/IGF-I stimulation. Interestingly, overexpression of constitutively active FOXO1 also led to activation of MEK and Akt phosphorylation. IGF-I-stimulated MEK and Akt phosphorylation were augmented byoverexpression of constitutively active FOXO1. These findings indicate bidirectional regulation of insulin/IGF-I receptor signaling and FOXO1 in cardiomyocytes. FOXO1 may provide feedback control through upregulation of insulin and IGF-I receptor signaling.

Objects referenced in this article
Gene Insr insulin receptor Rattus norvegicus

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