Horm Metab Res 2014; 46(06): 397-403
DOI: 10.1055/s-0033-1363981
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Insulin Stimulates the Expression of the SHARP-1 Gene via Multiple Signaling Pathways

K. Takagi
1   Department of Health and Nutritional Science, Faculty of Human Health Science, Matsumoto University, Matsumoto, Nagano­, Japan
,
K. Asano
1   Department of Health and Nutritional Science, Faculty of Human Health Science, Matsumoto University, Matsumoto, Nagano­, Japan
,
A. Haneishi
1   Department of Health and Nutritional Science, Faculty of Human Health Science, Matsumoto University, Matsumoto, Nagano­, Japan
,
M. Ono
2   Matsumoto University Graduate School of Health Science, Matsumoto, Nagano, Japan
,
Y. Komatsu
2   Matsumoto University Graduate School of Health Science, Matsumoto, Nagano, Japan
,
T. Yamamoto
3   Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani ­University, Tondabayashi, Osaka, Japan
,
T. Tanaka
3   Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani ­University, Tondabayashi, Osaka, Japan
,
H. Ueno
4   Department of Biochemistry and Molecular Pathophysiology, University of Occupational and Environmental Health, School of Medicine, ­Yahata-nishi-ku, Kitakyushu, Fukuoka, Japan
,
W. Ogawa
5   Department of Clinical Molecular Medicine, Division of Diabetes and ­Digestive and Kidney Diseases, Kobe University Graduate School of ­Medicine, Chuo-ku, Kobe, Japan
,
K. Tomita
3   Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani ­University, Tondabayashi, Osaka, Japan
,
T. Noguchi
3   Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani ­University, Tondabayashi, Osaka, Japan
,
K. Yamada
1   Department of Health and Nutritional Science, Faculty of Human Health Science, Matsumoto University, Matsumoto, Nagano­, Japan
2   Matsumoto University Graduate School of Health Science, Matsumoto, Nagano, Japan
› Author Affiliations
Further Information

Publication History

received 03 October 2013

accepted 16 December 2013

Publication Date:
20 January 2014 (online)

Abstract

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.