Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 103 (22): 8408-8413

Copyright © 2006 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / DEVELOPMENTAL BIOLOGY

Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells

Ryan B. Corcoran, and Matthew P. Scott*

Departments of Developmental Biology, Genetics, and Bioengineering, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5329

Contributed by Matthew P. Scott, April 11, 2006

Abstract: Sterol synthesis is required for Sonic hedgehog (Shh) signal transduction. Errors in Shh signal transduction play important roles in the formation of human tumors, including medulloblastoma (MB). It is not clear which products of sterol synthesis are necessary for Shh signal transduction or how they act. Here we show that cholesterol or specific oxysterols are the critical products of sterol synthesis required for Shh pathway signal transduction in MB cells. In MB cells, sterol synthesis inhibitors reduce Shh target gene transcription and block Shh pathway-dependent proliferation. These effects of sterol synthesis inhibitors can be reversed by exogenous cholesterol or specific oxysterols. We also show that certain oxysterols can maximally activate Shh target gene transcription through the Smoothened (Smo) protein as effectively as the known Smo full agonist, SAG. Thus, sterols are required and sufficient for Shh pathway activation. These results suggest that oxysterols may be critical regulators of Smo, and thereby Shh signal transduction. Inhibition of Shh signaling by sterol synthesis inhibitors may offer a novel approach to the treatment of MB and other Shh pathway-dependent human tumors.

Key Words: Smoothened • Patched • sterol synthesis pathway • cholesterol • cancer


Freely available online through the PNAS open access option.

Author contributions: R.B.C. and M.P.S. designed research; R.B.C. performed research; R.B.C. analyzed data; and R.B.C. and M.P.S. wrote the paper.

Conflict of interest statement: No conflicts declared.

*To whom correspondence should be addressed. E-mail: mscott{at}stanford.edu

© 2006 by The National Academy of Sciences of the USA


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Tracking the Subcellular Fate of 20(S)-Hydroxycholesterol with Click Chemistry Reveals a Transport Pathway to the Golgi.
S. M. Peyrot, S. Nachtergaele, G. Luchetti, L. K. Mydock-McGrane, H. Fujiwara, D. Scherrer, A. Jallouk, P. H. Schlesinger, D. S. Ory, D. F. Covey, et al. (2014)
J. Biol. Chem. 289, 11095-11110
   Abstract »    Full Text »    PDF »
A novel site comes into sight.
(2013)
eLife Sci 2, e01680
The Major Brain Cholesterol Metabolite 24(S)-Hydroxycholesterol Is a Potent Allosteric Modulator of N-Methyl-D-Aspartate Receptors.
S. M. Paul, J. J. Doherty, A. J. Robichaud, G. M. Belfort, B. Y. Chow, R. S. Hammond, D. C. Crawford, A. J. Linsenbardt, H.-J. Shu, Y. Izumi, et al. (2013)
J. Neurosci. 33, 17290-17300
   Abstract »    Full Text »    PDF »
Discovery, Molecular and Pharmacological Characterization of GSA-10, a Novel Small-Molecule Positive Modulator of Smoothened.
T. Gorojankina, L. Hoch, H. Faure, H. Roudaut, E. Traiffort, A. Schoenfelder, N. Girard, A. Mann, F. Manetti, A. Solinas, et al. (2013)
Mol. Pharmacol. 83, 1020-1029
   Abstract »    Full Text »    PDF »
Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling.
S. Nachtergaele, D. M. Whalen, L. K. Mydock, Z. Zhao, T. Malinauskas, K. Krishnan, P. W. Ingham, D. F. Covey, C. Siebold, and R. Rohatgi (2013)
eLife Sci 2, e01340
   Abstract »    Full Text »    PDF »
The Hedgehog Signal Transduction Network.
D. J. Robbins, D. L. Fei, and N. A. Riobo (2012)
Science Signaling 5, re6
   Abstract »    Full Text »    PDF »
Role of Hedgehog Signaling in Malignant Pleural Mesothelioma.
Y. Shi, U. Moura, I. Opitz, A. Soltermann, H. Rehrauer, S. Thies, W. Weder, R. A. Stahel, and E. Felley-Bosco (2012)
Clin. Cancer Res. 18, 4646-4656
   Abstract »    Full Text »    PDF »
Targeting hedgehog in hematologic malignancy.
D. A. Irvine and M. Copland (2012)
Blood 119, 2196-2204
   Abstract »    Full Text »    PDF »
Vitamin D3 Inhibits Hedgehog Signaling and Proliferation in Murine Basal Cell Carcinomas.
J. Y. Tang, T. Z. Xiao, Y. Oda, K. S. Chang, E. Shpall, A. Wu, P.-L. So, J. Hebert, D. Bikle, and E. H. Epstein Jr. (2011)
Cancer Prevention Research 4, 744-751
   Abstract »    Full Text »    PDF »
Malformation syndromes caused by disorders of cholesterol synthesis.
F. D. Porter and G. E. Herman (2011)
J. Lipid Res. 52, 6-34
   Abstract »    Full Text »    PDF »
A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes.
H. Tukachinsky, L. V. Lopez, and A. Salic (2010)
J. Cell Biol. 191, 415-428
   Abstract »    Full Text »    PDF »
Sonic Hedgehog Signaling Induces Vascular Smooth Muscle Cell Proliferation via Induction of the G1 Cyclin-Retinoblastoma Axis.
F. Li, M. Duman-Scheel, D. Yang, W. Du, J. Zhang, C. Zhao, L. Qin, and S. Xin (2010)
Arterioscler Thromb Vasc Biol 30, 1787-1794
   Abstract »    Full Text »    PDF »
Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies.
M. Mimeault and S. K. Batra (2010)
Pharmacol. Rev. 62, 497-524
   Abstract »    Full Text »    PDF »
Antipsychotic Drugs Regulate Hedgehog Signaling by Modulation of 7-Dehydrocholesterol Reductase Levels.
M. Lauth, V. Rohnalter, A. Bergstrom, M. Kooshesh, P. Svenningsson, and R. Toftgard (2010)
Mol. Pharmacol. 78, 486-496
   Abstract »    Full Text »    PDF »
Common Botanical Compounds Inhibit the Hedgehog Signaling Pathway in Prostate Cancer.
A. Slusarz, N. S. Shenouda, M. S. Sakla, S. K. Drenkhahn, A. S. Narula, R. S. MacDonald, C. L. Besch-Williford, and D. B. Lubahn (2010)
Cancer Res. 70, 3382-3390
   Abstract »    Full Text »    PDF »
The Hedgehog morphogen in myocardial ischemia-reperfusion injury.
M. F. Bijlsma and C. A. Spek (2010)
Experimental Biology and Medicine 235, 447-454
   Abstract »    Full Text »    PDF »
Patched regulates Smoothened trafficking using lipoprotein-derived lipids.
H. Khaliullina, D. Panakova, C. Eugster, F. Riedel, M. Carvalho, and S. Eaton (2009)
Development 136, 4111-4121
   Abstract »    Full Text »    PDF »
Tuberous Sclerosis Complex Suppression in Cerebellar Development and Medulloblastoma: Separate Regulation of Mammalian Target of Rapamycin Activity and p27Kip1 Localization.
B. Bhatia, P. A. Northcott, D. Hambardzumyan, B. Govindarajan, D. J. Brat, J. L. Arbiser, E. C. Holland, M. D. Taylor, and A. M. Kenney (2009)
Cancer Res. 69, 7224-7234
   Abstract »    Full Text »    PDF »
Variations in Hedgehog signaling: divergence and perpetuation in Sufu regulation of Gli.
L. Ruel and P. P. Therond (2009)
Genes & Dev. 23, 1843-1848
   Abstract »    Full Text »    PDF »
Converse Conformational Control of Smoothened Activity by Structurally Related Small Molecules.
H. Yang, J. Xiang, N. Wang, Y. Zhao, J. Hyman, S. Li, J. Jiang, J. K. Chen, Z. Yang, and S. Lin (2009)
J. Biol. Chem. 284, 20876-20884
   Abstract »    Full Text »    PDF »
Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation.
Y. Wang, Z. Zhou, C. T. Walsh, and A. P. McMahon (2009)
PNAS 106, 2623-2628
   Abstract »    Full Text »    PDF »
Two Patched Protein Subtypes and a Conserved Domain of Group I Proteins That Regulates Turnover.
S. Kawamura, K. Hervold, F.-A. Ramirez-Weber, and T. B. Kornberg (2008)
J. Biol. Chem. 283, 30964-30969
   Abstract »    Full Text »    PDF »
Hedgehog: functions and mechanisms.
M. Varjosalo and J. Taipale (2008)
Genes & Dev. 22, 2454-2472
   Abstract »    Full Text »    PDF »
Hedgehog signalling in endocrine development and disease.
P. J King, L. Guasti, and E. Laufer (2008)
J. Endocrinol. 198, 439-450
   Abstract »    Full Text »    PDF »
Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network.
E. Dessaud, A. P. McMahon, and J. Briscoe (2008)
Development 135, 2489-2503
   Abstract »    Full Text »    PDF »
A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1+ smooth muscle progenitor cells.
J. N. Passman, X. R. Dong, S.-P. Wu, C. T. Maguire, K. A. Hogan, V. L. Bautch, and M. W. Majesky (2008)
PNAS 105, 9349-9354
   Abstract »    Full Text »    PDF »
Phosphorylation of the atypical kinesin Costal2 by the kinase Fused induces the partial disassembly of the Smoothened-Fused-Costal2-Cubitus interruptus complex in Hedgehog signalling.
L. Ruel, A. Gallet, S. Raisin, A. Truchi, L. Staccini-Lavenant, A. Cervantes, and P. P. Therond (2007)
Development 134, 3677-3689
   Abstract »    Full Text »    PDF »
Deconstructing the Hedgehog Pathway in Development and Disease.
L. Jacob and L. Lum (2007)
Science 318, 66-68
   Abstract »    Full Text »    PDF »
Lipoproteins and their receptors in embryonic development: more than cholesterol clearance.
T. E. Willnow, A. Hammes, and S. Eaton (2007)
Development 134, 3239-3249
   Abstract »    Full Text »    PDF »
Patched1 Regulates Hedgehog Signaling at the Primary Cilium.
R. Rohatgi, L. Milenkovic, and M. P. Scott (2007)
Science 317, 372-376
   Abstract »    Full Text »    PDF »
Oxysterols Are Novel Activators of the Hedgehog Signaling Pathway in Pluripotent Mesenchymal Cells.
J. R. Dwyer, N. Sever, M. Carlson, S. F. Nelson, P. A. Beachy, and F. Parhami (2007)
J. Biol. Chem. 282, 8959-8968
   Abstract »    Full Text »    PDF »
Hedgehog signaling.
M. Varjosalo and J. Taipale (2007)
J. Cell Sci. 120, 3-6
   Full Text »    PDF »
Human Receptors Patched and Smoothened Partially Transduce Hedgehog Signal When Expressed in Drosophila Cells.
M. De Rivoyre, L. Ruel, M. Varjosalo, A. Loubat, M. Bidet, P. Therond, and I. Mus-Veteau (2006)
J. Biol. Chem. 281, 28584-28595
   Abstract »    Full Text »    PDF »
The C-terminal tail of the Hedgehog receptor Patched regulates both localization and turnover.
X. Lu, S. Liu, and T. B. Kornberg (2006)
Genes & Dev. 20, 2539-2551
   Abstract »    Full Text »    PDF »
Activation of heterotrimeric G proteins by Smoothened.
N. A. Riobo, B. Saucy, C. DiLizio, and D. R. Manning (2006)
PNAS 103, 12607-12612
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882