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Vol. 273, Issue 2, 917-923, January 9, 1998

Insulin Stimulates cAMP-response Element Binding Protein Activity in HepG2 and 3T3-L1 Cell Lines

Dwight J. Klemm^§, William J. Roesler, Tracy Boras^**, Lillester A. Colton, Kimberly Felder^**, and Jane E-B. Reusch^**

From the  Department of Allergy and Clinical Immunology, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, the ^** Research Service, Veterans Affairs Medical Center, Denver, Colorado 80220, the ^§ Departments of Biochemistry and Molecular Genetics and  Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80220, and the  Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N-5E5

Earlier studies from our laboratory demonstrated an insulin-mediated increase in cAMP-response element binding protein (CREB) phosphorylation. In this report, we show that insulin stimulates both CREB phosphorylation and transcriptional activation in HepG2 and 3T3-L1 cell lines, models of insulin-sensitive tissues. Insulin stimulated the phosphorylation of CREB at serine 133, the protein kinase A site, and mutation of serine 133 to alanine blocked the insulin effect.

Many of the signaling pathways known to be activated by insulin have been implicated in CREB phosphorylation and activation. The ability of insulin to induce CREB phosphorylation and activity was efficiently blocked by PD98059, a potent inhibitor of mitogen-activated protein kinase kinase (MEK1), but not significantly by rapamycin or wortmannin. Likewise, expression of dominant negative forms of Ras or Raf-1 completely blocked insulin-stimulated CREB transcriptional activity. Finally, we demonstrate an essential role for CREB in insulin activation of fatty-acid synthase and fatty acid binding protein (FABP) indicating the potential physiologic relevance of insulin regulation of CREB.

In summary, insulin regulates CREB transcriptional activity in insulin-sensitive tissues via the Raf  MEK pathway and has an impact on physiologically relevant genes in these cells.

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