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J. Biol. Chem., Vol. 276, Issue 17, 13822-13829, April 27, 2001

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Epidermal Growth Factor Induction of Apolipoprotein A-I Is Mediated by the Ras-MAP Kinase Cascade and Sp1^*

Xi-Long Zheng^§¶, Shuji Matsubara^§, Catherine Diao^§, Morley D. Hollenberg, and Norman C. W. Wong^§**

From the Endocrine Research Group,  Departments of Medicine and ^§ Biochemistry & Molecular Biology and  Pharmacology & Therapeutics, the Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Insulin induces apolipoprotein A-I, apoA-I gene transcription via a membrane receptor with intrinsic tyrosine kinase activity. This finding prompted us to ask whether the gene is stimulated by epidermal growth factor (EGF), EGF a peptide hormone that binds to another member of the receptor superfamily with tyrosine kinase activity. Our data showed that like insulin, EGF increased abundance of apoA-I protein and transcription of the gene in human hepatoma, Hep G2 cells. The effects of both hormones appeared direct because their induction of apoA-I gene transcription was not affected by the protein synthesis inhibitor, cycloheximide. Although both insulin and EGF stimulate apoA-I expression, each hormone binds to a distinct membrane receptor thus suggesting differential intracellular signaling. Therefore, we used a panel of inhibitors to define the pathway(s) that mediate the actions of these hormones. Whereas, the actions of EGF required only the Ras-mitogen-activated protein, MAP kinase, those of insulin were mediated by equal participation of both the Ras-MAP kinase and protein kinase C, PKC cascades. Despite differences in signaling pathways triggered by each hormone receptor, the activation of apoA-I transcription required the participation of a single transcription factor, Sp1. Furthermore, EGF induction of transcription was attenuated by mutating the MAP kinase site at amino acid, Thr²⁶⁶ rendering Sp1 phosphorylation deficient. In summary, EGF stimulation of apoA-I expression is mediated solely by the Ras-MAP kinase cascade and enhanced activity of this pathway requires Sp1 with an intact phosphorylation site at Thr²⁶⁶. However, insulin induction of this gene is different and requires both Ras-MAP kinase and PKC pathways but their actions are also mediated by Sp1.

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