Abstract
Sonic hedgehog, Patched and Gli are components of a mammalian signalling pathway that has been conserved during evolution and which has a central role in the control of pattern formation and cellular proliferation during development. Here we identify the human Suppressor-of-Fused (SUFUH) complementary DNA and show that the gene product interacts physically with the transcriptional effector GLI-1, can sequester GLI-1 in the cytoplasm, but can also interact with GLI-1 on DNA. Functionally, SUFUH inhibits transcriptional activation by GLI-1, as well as osteogenic differentiation in response to signalling from Sonic hedgehog. Localization of GLI-1 is influenced by the presence of a nuclear-export signal, and GLI-1 becomes constitutively nuclear when this signal is mutated or nuclear export is inhibited. These results show that SUFUH is a conserved negative regulator of GLI-1 signalling that may affect nuclear–cytoplasmic shuttling of GLI-1 or the activity of GLI-1 in the nucleus and thereby modulate cellular responses.
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References
Roessler, E. et al. Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly. Hum. Mol. Genet. 6, 1847–1853 (1997).
Hahn, H. et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851 (1996).
Johnson, R. L. et al. Human homolog of patched, a candidate gene for basal cell nevus syndrome. Science 272, 1668–1671 (1996).
Vortkamp, A., Gessler, M. & Grzeschik, K.-H. GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature 352, 539–540 (1991).
Ruiz i Altaba, A. Catching a gli-mpse of hedgehog. Cell 90, 193–196 (1997).
Monnier, V., Dussillol, F., Alves, G., Lamour-Isnard, C. & Plessis, A. Suppressor of fused links Fused and Cubitus interruptus on the hedgehog signalling pathway. Curr. Biol. 8, 583–586 (1998).
Methot, N. & Basler, K. Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. Cell 96, 819–831 (1999).
Ohlmeyer, J. & Kalderon, D. Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator. Nature 396, 749–753 (1998).
Shin, S. H., Kogerman, P., Lindström, E., Toftgård, R. & Biesecker, L. G. GLI3 mutations in human disorders mimic Drosophila Cubitus interruptus protein functions and localization. Proc. Natl Acad. Sci. USA 96, 2880–2884 (1999).
Kinzler, K. W. & Vogelstein, B. The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. Mol. Cell. Biol. 10, 634–642 (1990).
Dahmane, N., Lee, J., Robins, P., Heller, P. & Ruiz i Altaba, A. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 389, 876–881 (1997).
Ruiz i Altaba, A. Gli proteins encode context-dependent positive and negative functions: implications for development and disease. Development 126, 3205–3216 (1999).
Dai, P., Akimaru, H., Tanaka, Y., Maekawa, T., Nakafuku, M. & Ishii, S. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J. Biol. Chem. 274, 8143–8152 (1999).
Pham, A. et al. The Suppressor of fused gene encodes a novel PEST protein involved in Drosophila segment polarity establishment. Genetics 140, 587–598 (1995).
Vortkamp, A. et al. Regulation of cartilage differentiation by Indian Hedgehog and PTCH-related protein. Science 273, 613–622 (1996).
Vortkamp, A. et al. Recapitulation of signals regulating embryonic bone formation during postnatal growth and in fracture repair. Mech. Dev. 71, 65–76 (1998).
Hynes, M. et al. Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1. Neuron 19, 15–26 (1997).
Kinzler, K. W., Ruppert, J. M., Bigner, S. H. & Vogelstein, B. The GLI gene is a member of the Kruppel family of zinc finger proteins. Nature 332, 371–374 (1988).
Nakamura, T. et al. Induction of osteogenic differentiation by hedgehog proteins. Biochem. Biophys. Res. Commun. 237, 465–469 (1997).
Murone, M., Rosenthal, A. & de Sauvage, F. J. Sonic hedgehog signaling by the patched-smoothened receptor complex. Curr. Biol. 9, 76–84 (1999).
Aza-Blanc, P., Ramirez-Weber, F. A., Laget, M. P., Schwartz, C. & Kornberg, T. B. Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell 89, 1043–1053 (1997).
Bogerd, H., Echarri, A., Ross, T. M. & Cullen, B. R. Inhibition of human immunodeficiency virus Rev and human T-cell leukemia virus Rex function, but not Mason-Pfizer monkey virus constitutive transport element activity, by a mutant human nucleoporin targeted to Crm1. J. Virol. 72, 8627–8635 (1998).
Kudo, N. et al. Leptomycin B inhibition of signal-mediated nuclear export by direct binding to CRM1. Exp. Cell Res. 242, 540–547 (1998).
Ingham, P. W. Transducing hedgehog: the story so far. EMBO J. 17, 3505–3511 (1998).
Hamada, F. et al. Negative regulation of Wingless signaling by D-axin, a Drosophila homolog of axin. Science 283, 1739–1742 (1999).
Ruppert, J., Vogelstein, B. & Kinzler, K. W. The zinc finger protein GLI transforms primary cells in cooperation with adenovirus E1A. Mol. Cell. Biol. 11, 1724–1728 (1991).
Zaphiropoulos, P. G. & Toftgard, R. cDNA cloning of a novel WD repeat protein mapping to the 9q22.3 chromosomal region. DNA Cell Biol. 15, 1049–1056 (1996).
Wilkinson, D. G. In Situ Hybridization: A Practical Approach (IRL, Oxford, 1992).
Undén, A. B., Zaphiropoulos, P. G., Bruce, K., Toftgård, R. & Ståhle-Bäckdahl, M. Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma. Cancer Res. 57, 2336–2340 (1997).
Evan, G. I., Lewis, G. K., Ramsay, G. & Bishop, J. M. Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product. Mol Cell Biol 5, 3610–3616 (1985).
Pati, U. K. Novel vectors for expression of cDNA encoding epitope-tagged proteins in mammalian cells. Gene 114, 285–288 (1992).
Almlöf, T., Gustafsson, J.-Å . & Wright, A. P. H. Role of hydrophobic amino acid clusters in the transactivation activity of the human glucocorticoid receptor. Mol. Cell. Biol. 17, 934–945 (1997).
Ausubel, F. M. et al. Current Protocols in Molecular Biology (John Wiley, New York, 1987).
Pavletich, N. P. & Pabo, C. O. Crystal structure of a five-finger GLI-DNA complex: new perspectives on zinc fingers. Science 261, 1701–1707 (1993).
Acknowledgements
We thank B.Vogelstein, K. W. Kinzler, A. McMahon, T. Almlöf and A. Wright for constructs, and B. Wolff for the donation of leptomycin B. This study was supported by grants from the Swedish Cancer Fund (to R.T. and P.G.Z.), the Swedish Children Cancer Fund and the Swedish National Radiation Protection Board (to R.T.) and the Welander-Finsen Foundation, the Cancer Society and Svenska Läkarsällskapet (to A.B.U.). P.K. is a recipient of guest researcher fellowships from the Swedish Institute and Karolinska Institute, T.G. of a postdoctoral TMR fellowship, and D.K. of a postdoctoral fellowship from the Wennergren Foundation.
Correspondence and requests for materials should be addressed to R.T. The SUFUH cDNA sequence has been deposited at GenBank under accession number AF175770.
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Kogerman, P., Grimm, T., Kogerman, L. et al. Mammalian Suppressor-of-Fused modulates nuclear–cytoplasmic shuttling of GLI-1. Nat Cell Biol 1, 312–319 (1999). https://doi.org/10.1038/13031
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DOI: https://doi.org/10.1038/13031
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