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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ruiz i Altaba, A. Gli proteins and Hedgehog signaling: development and cancer. Trends Genet. 15, 418–425 (1999)
Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995)
Wolff, T. & Ready, D. F. in The Development of Drosophila melanogaster (ed. Bate, M.Arias, A. M.) 1277–1326 (Cold Spring Harbor Laboratory Press, Plainview, New York, 1993)
Dyson, N. The regulation of E2F by pRB-family proteins. Genes Dev. 12, 2245–2262 (1998)
Xin, S., Weng, L., Xu, J. & Du, W. The role of RBF in developmentally regulated cell proliferation in the eye disc and in Cyclin D/Cdk4 induced cellular growth. Development 129, 1345–1356 (2002)
McMahon, A. P. More surprises in the Hedgehog signaling pathway. Cell 100, 185–188 (2000)
Huang, Z. & Kunes, S. Signals transmitted along retinal axons in Drosophila: Hedgehog signal reception and the cell circuitry of lamina cartridge assembly. Development 125, 3753–3764 (1998)
Finley, R. L. Jr, Thomas, B. J., Zipursky, S. L. & Brent, R. Isolation of Drosophila cyclin D, a protein expressed in the morphogenetic furrow before entry into S phase. Proc. Natl Acad. Sci. USA 93, 3011–3015 (1996)
Knoblich, J. A. et al. Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation. Cell 77, 107–120 (1994)
Ewen, M. E. Where the cell cycle and histones meet. Genes Dev. 14, 2265–2270 (2000)
Lane, M. E. et al. Dacapo, a cyclin-dependent kinase inhibitor, stops cell proliferation during Drosophila development. Cell 87, 1225–1235 (1996)
de Nooij, J. C., Letendre, M. A. & Hariharan, I. K. A cyclin-dependent kinase inhibitor, Dacapo, is necessary for timely exit from the cell cycle during Drosophila embryogenesis. Cell 87, 1237–1247 (1996)
Jones, L., Richardson, H. & Saint, R. Tissue-specific regulation of cyclin E transcription during Drosophila melanogaster embryogenesis. Development 127, 4619–4630 (2000)
Zarkower, D. & Hodgkin, J. Zinc fingers in sex determination: only one of the two C. elegans Tra-1 proteins binds DNA in vitro. Nucleic Acids Res. 21, 3691–3698 (1993)
Secombe, J., Pispa, J., Saint, R. & Richardson, H. Analysis of a Drosophila cyclin E hypomorphic mutation suggests a novel role for cyclin E in cell proliferation control during eye imaginal disc development. Genetics 149, 1867–1882 (1998)
Stocker, H. & Hafen, E. Genetic control of cell size. Curr. Opin. Genet. Dev. 10, 529–535 (2000)
Neufeld, T. P., de la Cruz, A. F., Johnston, L. A. & Edgar, B. A. Coordination of growth and cell division in the Drosophila wing. Cell 93, 1183–1193 (1998)
Datar, S. A., Jacobs, H. W., de La Cruz, A. F., Lehner, C. F. & Edgar, B. A. The Drosophila cyclin D–cdk4 complex promotes cellular growth. EMBO J. 19, 4543–4554 (2000)
Meyer, C. A. et al. Drosophila cdk4 is required for normal growth and is dispensable for cell cycle progression. EMBO J. 19, 4533–4542 (2000)
Johnson, R. L., Grenier, J. K. & Scott, M. P. patched overexpression alters wing disc size and pattern: transcriptional and post-transcriptional effects on hedgehog targets. Development 121, 4161–4170 (1995)
Kenney, A. M. & Rowitch, D. H. Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol. Cell. Biol. 20, 9055–90567 (2000)
Milenkovic, L., Goodrich, L. V., Higgins, K. M. & Scott, M. P. Mouse patched1 controls body size determination and limb patterning. Development 126, 4431–4440 (1999)
Fantl, V., Stamp, G., Andrews, A., Rosewell, I. & Dickson, C. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev. 9, 2364–2372 (1995)
Donnellan, R. & Chetty, R. Cyclin E in human cancers. FASEB J. 13, 773–780 (1999)
Wang, T. C. et al. Mammary hyperplasia and carcinoma in MMTV–cyclin D1 transgenic mice. Nature 369, 669–671 (1994)
Xu, T. & Rubin, G. M. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117, 1223–1237 (1993)
Struhl, G. & Basler, K. Organizing activity of wingless protein in Drosophila. Cell 72, 527–540 (1993)
Patel, N. in In situ Hybridization to Whole Mount Drosophila Embryos (ed. Krieg, P. A.) 357–370 (Wiley-Liss, New York, 1996)
Bosco, G., Du, W. & Orr-Weaver, T. L. DNA replication control through interaction of E2F-RB and the origin recognition complex. Nature Cell Biol. 3, 289–295 (2001)
Johnston, L. A. & Edgar, B. A. Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing. Nature 394, 82–84 (1998)
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.
The authors declare that they have no competing financial interests.
About this article
Cite this article
Duman-Scheel, M., Weng, L., Xin, S. et al. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature 417, 299–304 (2002). https://doi.org/10.1038/417299a
Genetic landscape and ligand-dependent activation of sonic hedgehog-Gli1 signaling in chordomas: a novel therapeutic target
Brain Pathology (2020)
Itraconazole inhibits the Hedgehog signaling pathway thereby inducing autophagy-mediated apoptosis of colon cancer cells
Cell Death & Disease (2020)
Acute Alcohol Intoxication Impairs Sonic Hedgehog‐Gli1 Signaling and Activation of Primitive Hematopoietic Precursor Cells in the Early Stage of Host Response to Bacteremia
Alcoholism: Clinical and Experimental Research (2020)
Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids
Journal of Experimental & Clinical Cancer Research (2020)