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Published online 5 April 2004. doi:10.1083/jcb.200401004
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 1, 77-86
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Article

 PI-3K and Akt are mediators of AP-1 induction by 5-MCDE in mouse epidermal Cl41 cells

Jingxia Li1, Haobin Chen1, Moon-Shong Tang1, Xianglin Shi2, Shantu Amin3, Dhimant Desai3, Max Costa1, and Chuanshu Huang1,2

1 Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987
2 Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai 200031, China
3 American Health Foundation Cancer Center, Institute for Cancer Prevention, Valhalla, NY 10595

Address correspondence to C. Huang, Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Rd., Tuxedo, NY 10987. Tel.: (845) 731-3519. Fax: (845) 351-2118. email: chuanshu{at}env.med.nyu.edu

5-Methylchrysene has been found to be a complete carcinogen in laboratory animals. However, the tumor promotion effects of (±)-anti-5-methylchrysene-1,2-diol-3,4-epoxide (5-MCDE) remain unclear. In the present work, we found that 5-MCDE induced marked activator protein-1 (AP-1) activation in Cl41 cells. 5-MCDE also induced a marked activation of phosphatidylinositol 3-kinase (PI-3K). Inhibition of PI-3K impaired 5-MCDE–induced AP-1 transactivation, suggesting that PI-3K is an upstream kinase involved in AP-1 activation by 5-MCDE. Furthermore, we found that Akt is a PI-3K downstream mediator for 5-MCDE–induced AP-1 transactivation, whereas another PI-3K downstream kinase, p70S6K, was not involved in AP-1 activation by 5-MCDE. Moreover, inhibition of Akt activation blocked 5-MCDE–induced activation of extracellular signal–regulated protein kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs), whereas it did not affect p38K activation. Consistently, overexpression of a dominant-negative mutant of ERK2 or JNK1 blocked the AP-1 activation by 5-MCDE. These results demonstrate that 5-MCDE is able to induce AP-1 activation, and the AP-1 induction is specifically through a PI-3K/Akt–dependent and p70S6K-independent pathway.

Key Words: polycyclic aromatic hydrocarbons; signal transduction; protein kinases; transcription factor; tumor promotion

J. Li and H. Chen contributed equally to this work.

Abbreviations used in this paper: 5-MCDE, (±)-anti-5-methylchrysene-1,2-diol-3,4-epoxide; AP-1, activator protein-1; B[a]P, benzo[a]pyrene; B[a]PDE, (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide; ERK, extracellular signal–regulated protein kinase; JNK, c-Jun NH2-terminal kinase; PAH, polycyclic aromatic hydrocarbon; TPA, 12-O-tetradecanoylphorbol-13-acetate.


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