Although mutations that activate the Hedgehog (Hh) signalling pathway have been linked to several types of cancer1, the molecular and cellular basis of Hh's ability to induce tumour formation is not well understood. We identified a mutation in patched (ptc), an inhibitor of Hh signalling, in a genetic screen for regulators of the Retinoblastoma (Rb) pathway in Drosophila. Here we show that Hh signalling promotes transcription of Cyclin E and Cyclin D, two inhibitors of Rb2, and principal regulators of the cell cycle during development in Drosophila. Upregulation of Cyclin E expression, accomplished through binding of Cubitus interruptus (Ci) to the Cyclin E promoter, mediates the ability of Hh to induce DNA replication. Upregulation of Cyclin D expression by Hh mediates the distinct ability of Hh to promote cellular growth. The discovery of a direct connection between Hh signalling and principal cell-cycle regulators provides insight into the mechanism by which deregulated Hh signalling promotes tumour formation.
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The authors declare that they have no competing financial interests.
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We thank J. Jiang, B. Edgar, C. Lehner, R. Holmgren, H. Richardson, T. Kornberg and the Bloomington Stock Center for providing fly stocks and antibodies used in this study. We gratefully acknowledge C. Heitzig and M. Giorgianni, who performed preliminary experiments that contributed to this work. C. Gudanowski provided technical assistance. We thank E. Williamson and the University of Chicago scanning electron microscope facility, as well as J. Auger and the University of Chicago Flow Cytometry Facility, for their technical advice. We are grateful for discussions with members of the Du lab, the Patel lab, and the Center for Molecular Oncology. Comments from C. Ferguson, A. Mahowald, N. Dyson and J. Duman aided us in the preparation of this manuscript. We thank B. Edgar for communicating results to us before publication. Grants from the American Cancer Society and the National Institutes of Health to W.D. supported this work.
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