Long-term exposure to nicotine, via ras pathway, induces cyclin D1 to stimulate G1 cell cycle transition.
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 G(1) phase of the cell cycle following serum starvation. The perturbation of the G(1) 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.
Chu
Michelle
M
Department of Pathology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Guo
Jinjin
J
Chen
Chang-Yan
CY
D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002460:Cell Line; D019938:Cyclin D1 / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004847:Epithelial Cells / Q000187:drug effects; D016193:G1 Phase; D008168:Lung / Q000166:cytology; D020935:MAP Kinase Signaling System; D051379:Mice; D009538:Nicotine / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D014157:Transcription Factors; D019938:Cyclin D1; D009538:Nicotine; D018631:ras Proteins