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Horm Metab Res. 2014 Jun;46(6):397-403. doi: 10.1055/s-0033-1363981. Epub 2014 Jan 20.

Insulin stimulates the expression of the SHARP-1 gene via multiple signaling pathways.

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Department of Health and Nutritional Science, Faculty of Human Health Science, Matsumoto University, Matsumoto, Nagano-, Japan.
Matsumoto University Graduate School of Health Science, Matsumoto, Nagano, Japan.
Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani -University, Tondabayashi, Osaka, Japan.
Department of Biochemistry and Molecular Pathophysiology, University of Occupational and Environmental Health, School of Medicine, -Yahata-nishi-ku, Kitakyushu, Fukuoka, Japan.
Department of Clinical Molecular Medicine, Division of Diabetes and -Digestive and Kidney Diseases, Kobe University Graduate School of -Medicine, Chuo-ku, Kobe, Japan.


The rat enhancer of split- and hairy-related protein-1 (SHARP-1) is a basic helix-loop-helix transcription factor. An issue of whether SHARP-1 is an insulin-inducible transcription factor was examined. Insulin rapidly increased the level of SHARP-1 mRNA both in vivo and in vitro. Then, signaling pathways involved with the increase of SHARP-1 mRNA by insulin were determined in H4IIE rat hepatoma cells. Pretreatments with LY294002, wortmannin, and staurosporine completely blocked the induction effect, suggesting the involvement of both phosphoinositide 3-kinase (PI 3-K) and protein kinase C (PKC) pathways. In fact, overexpression of a dominant negative form of atypical protein kinase C lambda (aPKCλ) significantly decreased the induction of the SHARP-1 mRNA. In addition, inhibitors for the small GTPase Rac or Jun N-terminal kinase (JNK) also blocked the induction of SHARP-1 mRNA by insulin. Overexpression of a dominant negative form of Rac1 prevented the activation by insulin. Furthermore, actinomycin D and cycloheximide completely blocked the induction of SHARP-1 mRNA by insulin. Finally, when a SHARP-1 expression plasmid was transiently transfected with various reporter plasmids into H4IIE cells, the promoter activity of PEPCK reporter plasmid was specifically decreased. Thus, we conclude that insulin induces the SHARP-1 gene expression at the transcription level via a both PI 3-K/aPKCλ/JNK- and a PI 3-K/Rac/JNK-signaling pathway; protein synthesis is required for this induction; and that SHARP-1 is a potential repressor of the PEPCK gene expression.

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