Abstract
The transcription factor E2F-1 plays a crucial role in the control of cellular growth. We previously reported its differential pattern of expression in human lung tumors. In this study, we have investigated the relationships linking the status of E2F-1 and a mediator of its proteasomal degradation, the S-phase kinase-associated protein 2 (Skp2) F-box protein. Using immunohistochemistry in a series of 129 lung tumors of all histological types, we demonstrate that Skp2 accumulates preferentially in high-grade neuroendocrine (HGNE) lung carcinomas (86%, P<0.0001), and show that Skp2 overexpression is associated with advanced stages (P<0.0001) and nodal metastasis (P<0.0001) in neuroendocrine (NE) lung tumors. Unexpectedly, we observe that Skp2 and E2F-1 expression directly correlates in NE lung tumors (P<0.0001). Moreover, using cellular models, we identify Skp2 as a new E2F-1 transcriptional target. Furthermore, we also provide evidence that Skp2 interacts physiologically with E2F-1 and stimulates its transcriptional activity toward the cyclin E promoter. Consistently, we demonstrate that cyclin E expression directly correlates with Skp2 (P<0.0001) and E2F-1 (P=0.0001) status in NE lung tumors. Overall, our data provide the first evidence of a direct and functional interconnection between the E2F-1, Skp2 and cyclin E oncoproteins in HGNE lung carcinomas.
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Acknowledgements
We thank Kristian Helin for providing us with the plasmid encoding E2F-1, Didier Trouche for the plasmid pGL2-cyclin E, Lars-Gunnar Larsson for the pcDNA3-Myc-Skp2 and Günter Schneider (Technical University of Munich, Munich, Germany) for the plasmid Skp2-luc. We thank Patricia Betton, Pascal Perron, Sylvie Veyrenc and Aurelie Micoud for technical assistance. This work was supported by grants from the Region Rhône Alpes (Thématique Prioritaire Cancer and Canceropole 2003: Oncocell, Epimed and INACancer) and by the Ligue Nationale contre le Cancer (Equipe Labellisée). CS was supported by a ‘poste accueil’ INSERM.
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Salon, C., Merdzhanova, G., Brambilla, C. et al. E2F-1, Skp2 and cyclin E oncoproteins are upregulated and directly correlated in high-grade neuroendocrine lung tumors. Oncogene 26, 6927–6936 (2007). https://doi.org/10.1038/sj.onc.1210499
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DOI: https://doi.org/10.1038/sj.onc.1210499
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