QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.096065v1 316/3/1255    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, S. K. Articles by Novak, R. F. Search for Related Content PubMed PubMed Citation Articles by Kim, S. K. Articles by Novak, R. F.

CELLULAR AND MOLECULAR

Identification of the Insulin Signaling Cascade in the Regulation of Alpha-Class Glutathione S-Transferase Expression in Primary Cultured Rat Hepatocytes

Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan

We reported previously that insulin elevated alpha-class glutathione S-transferase (GSTs) protein levels in primary cultured rat hepatocytes (Kim et al., 2003b). In contrast, glucagon down-regulated alpha- and pi-class GST expression, and mechanistic research implicated cAMP and protein kinase A in this process (Kim et al., 2003b). The present study examines the signaling pathways involved in the regulation of alpha-class GST in response to insulin in primary cultured rat hepatocytes. Protein levels of GSTA1/2 and GSTA3/5 and activity of GST toward 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD) were increased in an insulin concentration-dependent manner. Treatment of cells with the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] or rapamycin, an inhibitor of mammalian target of rapamycin and ribosomal p70 S6 kinase (p70S6K) phosphorylation, or with an adenovirus containing green fluorescent protein and a dominant-negative and kinase-dead Akt, effectively inhibited the insulin-mediated increase in alpha-class GST expression and GST activity toward NBD. In contrast, PD98059 (2'-amino-3'-methoxyflavone), an inhibitor of mitogen-activated protein kinase kinase, SP600125 (1,9-pyrazoloanthrone), an inhibitor of c-Jun N-terminal kinase, SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imadazole], an inhibitor of p38 mitogen-activated protein kinase, or bisindolylmaleimide, a broad spectrum inhibitor of protein kinase C, did not inhibit the insulin-mediated increase in alpha-class GST protein levels in hepatocytes. These results show that PI3K/Akt/p70S6K signaling is active in the insulin-mediated up-regulation of the antioxidant defense system and that low insulin levels, as encountered in diabetes, potentially increase the susceptibility of hepatocytes to xenobiotic-mediated and/or oxidative stress-mediated damage.

Address correspondence to: Dr. Raymond F. Novak, Institute of Environmental Health Sciences, Wayne State University, 2727 South Avenue, Room 4000, Detroit, MI 48201. E-mail: r.novak{at}wayne.edu

This article has been cited by other articles:

				Y. Luo, C. J. Dixon, J. F. Hall, P. J. White, and M. R. Boarder A Role for Akt in Epidermal Growth Factor-Stimulated Cell Cycle Progression in Cultured Hepatocytes: Generation of a Hyperproliferative Window after Adenoviral Expression of Constitutively Active Akt J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 884 - 891. [Abstract] [Full Text] [PDF]

				F. Lin, P. L. Zhang, X. J. Yang, J. W. Prichard, M. Lun, and R. E. Brown Morphoproteomic and Molecular Concomitants of an Overexpressed and Activated mTOR Pathway in Renal Cell Carcinomas Ann. Clin. Lab. Sci., January 1, 2006; 36(3): 283 - 293. [Abstract] [Full Text] [PDF]