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J. Biol. Chem., Vol. 280, Issue 8, 6369-6379, February 25, 2005

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Long-term Exposure to Nicotine, via Ras Pathway, Induces Cyclin D1 to Stimulate G₁ Cell Cycle Transition^*

Michelle Chu, Jinjin Guo, and Chang-Yan Chen

From the Department of Pathology, Boston University School of Medicine, Boston, Massachusetts 02118

Nicotine, a major component in tobacco, has been implicated as a potential factor that promotes the development of lung cancer. However, the molecular mechanism of its action is still unclear. In this study, we have shown that, via nicotinic acetylcholine receptors, persistent exposure of mouse epithelial cells to nicotine elicits Ras signaling and subsequent Raf/MAP kinase activity, accompanied by a significant increase in cyclin D1 promoter activity and its protein expression. AP-1 is required for activation of the cyclin D1 promoter. The induction of cyclin D1 expression and its promoter activity by nicotine is abolished by the suppression of Raf/MAP kinase signaling. Furthermore, upon nicotine treatment, the cells do not arrest in the G₁ phase of the cell cycle following serum starvation. The perturbation of the G₁ cell cycle checkpoint is caused by the deregulation of retinoblastoma/E2F activity. Therefore, our data indicated that by targeting the Ras pathway, long-term exposure to nicotine disrupts cell cycle restriction machinery and thus potentiates tumor development.

Received for publication, August 5, 2004 , and in revised form, December 1, 2004.

^* This work was supported by grants from the American Cancer Society (Alvan T. and Viola D. Fuller Research Fellowship) (to M. C.), from the National Institutes of Health (1R01CA100498), and the Department of Defense (W81XWH-04-1-0246) (to C-Y. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pathology, K522, Boston University School of Medicine, 80 E. Concord St., Boston, MA 02118. Tel.: 617-638-4128; Fax: 617-638-5673; E-mail: yanyan{at}bu.edu.

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