Title

Transcriptional repression of the C/EBP-α and GLUT4 genes in 3T3-L1 adipocytes by tumor necrosis factor-α. Regulation is coordinate and independent of protein synthesis

Document Type

Article

Publication Date

1-1-1992

Abstract

We have previously demonstrated the ability of tumor necrosis factor-α (TNF) to down-regulate the expression of GLUT4 (insulin-responsive glucose transporter) and C/EBP-α (CCAAT/enhancer-binding protein) (Stephens J. M., and Pekala, P. H. (1991) J. Biol. Chem. 266, 21839-21845). As C/EBP-α has been suggested to control GLUT4 expression, we have examined the time course for attenuation of transcription of these genes. Run-on transcription assays indicate a coordinate transcriptional repression of both GLUT4 and C/EBP-α genes (as well as the 422/aP2 gene, the adipocyte lipid-binding protein, whose expression has also been proposed to be controlled by C/EBP-α). Inhibition of transcription was observed within 1 h of TNF addition, with maximal suppression observed after 4 h. The inhibition was not blocked by cycloheximide. Okadaic acid treatment (1 h, 0.5 μM) also resulted in the coordinate transcriptional repression of the C/EBP-α, GLUT4, and 422/aP2 genes, consistent with involvement of a kinase-phosphatase system in the regulation of these genes. The decrease in C/EBP-α protein content was detectable 4 h after TNF addition and declined to 25% of controls within 24 h. A minor decrease in the protein content of GLUT4 was observed during the first 24 h of exposure to TNF; however, after 72 h of exposure GLUT4 protein was not detectable. The rapid coordinate transcriptional regulation of C/EBP- α, GLUT4, and 422/aP2 by TNF in the presence of cycloheximide suggests that the TNF-induced loss of GLUT4 protein may be mediated by a post-translational modification of an existing transcription factor. However, the rapid loss of C/EBP-α protein may be a contributing factor to further transcriptional suppression of the GLUT4 gene at the later time points. In addition to the transcriptional effect, we report that TNF-induced destabilization of these mRNAs contributes to decreased expression of all three genes.

Publication Source (Journal or Book title)

Journal of Biological Chemistry

First Page

13580

Last Page

13584

This document is currently not available here.

Share

COinS