Abstract
Germline mutations of APC in patients with Turcot syndrome (colon cancer and medulloblastoma), was well as somatic mutations of APC, β-catenin, and Axin in sporadic medulloblastomas (MBs) have shown the importance of WNT signaling in the pathogenesis of MB. A subset of children with MB have germline mutations of SUFU, a known inhibitor of Hedgehog signal transduction. A recent report suggested that murine Sufu can bind β-catenin, export it from the nucleus, and thereby repress β-catenin/T-cell factor (Tcf)-mediated transcription. We show that an MB-derived mutant of SUFU has lost the ability to decrease nuclear levels of β-catenin, and cannot inhibit β-catenin/Tcf-mediated transcription as compared to wild type SUFU. Our results suggest that loss of function of SUFU results in overactivity of both the Sonic Hedgehog, and the WNT signaling pathways, leading to excessive proliferation and failure to differentiate resulting in MB.
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References
Baeza N, Masuoka J, Kleihues P and Ohgaki H . (2003). Oncogene, 22, 632–636.
Borycki A, Brown AM and Emerson Jr CP . (2000). Development, 127, 2075–2087.
Cui H, Meng Y and Bulleit RF . (1998). Brain Res. Dev. Brain Res., 111, 177–188.
Dahmen RP, Koch A, Denkhaus D, Tonn JC, Sorensen N, Berthold F, Behrens J, Birchmeier W, Wiestler OD and Pietsch T . (2001). Cancer Res., 61, 7039–7043.
Dickinson ME, Krumlauf R and McMahon AP . (1994). Development, 120, 1453–1471.
Ding Q, Fukami S, Meng X, Nishizaki Y, Zhang X, Sasaki H, Dlugosz A, Nakafuku M and Hui C . (1999). Curr. Biol., 9, 1119–1122.
Eberhart CG, Tihan T and Burger PC . (2000). J. Neuropathol Exp. Neurol., 59, 333–337.
Evans G, Burnell L, Campbell R, Gattamaneni HR and Birch J . (1993). Med. Pediatr. Oncol., 21, 433–434.
Frayling IM, Beck NE, Ilyas M, Dove-Edwin I, Goodman P, Pack K, Bell JA, Williams CB, Hodgson SV, Thomas HJ, Talbot IC, Bodmer WF and Tomlinson IP . (1998). Proc. Natl. Acad. Sci. USA, 95, 10722–10727.
Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, Burger PC, Wood PA, Taqi F, Booker SV, Petersen GM, Offerhaus JA, Tersmette AC, Giardiello FM, Vogelstein B and Kinzler KW . (1995). N. Engl. J. Med., 332, 839–847.
Hart M, Concordet JP, Lassot I, Albert I, del los Santos R, Durand H, Perret C, Rubinfeld B, Margottin F, Benarous R and Polakis P . (1999). Curr. Biol., 9, 207–210.
Hart MJ, de los Santos R, Albert IN, Rubinfeld B and Polakis P . (1998). Curr. Biol., 8, 573–581.
Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P and Ohgaki H . (2000). Am. J. Pathol., 156, 433–437.
Iwao K, Nakamori S, Kameyama M, Imaoka S, Kinoshita M, Fukui T, Ishiguro S, Nakamura Y and Miyoshi Y . (1998). Cancer Res., 58, 1021–1026.
Jia J, Amanai K, Wang G, Tang J, Wang B and Jiang J . (2002). Nature, 416, 548–552.
Jiang J and Struhl G . (1998). Nature, 391, 493–496.
Kalderon D . (2002). Trends Cell Biol., 12, 523–531.
Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K, Nakamichi I, Kikuchi A and Nakayama K . (1999). EMBO J., 18, 2401–2410.
Koch A, Waha A, Tonn JC, Sorensen N, Berthold F, Wolter M, Reifenberger J, Hartmann W, Friedl W, Reifenberger G, Wiestler OD and Pietsch T . (2001). Int. J. Cancer, 93, 445–449.
Latres E, Chiaur DS and Pagano M . (1999). Oncogene, 18, 849–854.
Lee CS, Buttitta LA, May NR, Kispert A and Fan CM . (2000). Development, 127, 109–118.
Lum L, Yao S, Mozer B, Rovescalli A, Von Kessler D, Nirenberg M and Beachy PA . (2003). Science, 299, 2039–2045.
Mainprize TG, Taylor MD and Rutka JT . (2000). Clin. Neurosurg., 47, 259–302.
Maniatis T . (1999). Genes Dev., 13, 505–510.
Meng X, Poon R, Zhang X, Cheah A, Ding Q, Hui CC and Alman B . (2001). J. Biol. Chem., 276, 40113–40119.
Methot N and Basler K . (2000). Development, 127, 4001–4010.
Miller RW and Rubinstein JH . (1995). Am. J. Med. Genet., 56, 112–115.
Mori T, Nagase H, Horii A, Miyoshi Y, Shimano T, Nakatsuru S, Aoki T, Arakawa H, Yanagisawa A and Ushio Y . (1994). Genes Chromosomes Cancer, 9, 168–172.
Mullor JL, Dahmane N, Sun T and Ruiz i Altaba A . (2001). Curr. Biol., 11, 769–773.
Murone M, Luoh SM, Stone D, Li W, Gurney A, Armanini M, Grey C, Rosenthal A and de Sauvage FJ . (2000). Nat. Cell Biol., 2, 310–312.
Nakagawa H, Koyama K, Monden M and Nakamura Y . (1999). Jpn. J. Cancer Res., 90, 982–986.
Pearse II RV, Collier LS, Scott MP and Tabin CJ . (1999). Dev. Biol., 212, 323–336.
Price MA and Kalderon D . (2002). Cell, 108, 823–835.
Reddy S, Andl T, Bagasra A, Lu MM, Epstein DJ, Morrisey EE and Millar SE . (2001). Mech. Dev., 107, 69–82.
Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E and Polakis P . (1997). Science, 275, 1790–1792.
Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R and Ben-Ze'ev A . (1999). Proc. Natl. Acad. Sci. USA, 96, 5522–5527.
Skousen GJ, Wardinsky T and Chenaille P . (1996). Am. J. Med. Genet., 66, 367.
Steigerwald K, Santoro IM, Kordich JJ, Gismondi V, Trzepacz C, Badiali M, Giangaspero F, Balko MG, Graham JS, Ratner N, Lowy AM, Varesco L and Groden J . (2001). J. Med. Genet., 38, 257–262.
Stone DM, Murone M, Luoh S, Ye W, Armanini MP, Gurney A, Phillips H, Brush J, Goddard A, de Sauvage FJ and Rosenthal A . (1999). J. Cell Sci., 112 (Part 23), 4437–4448.
Takemaru KI and Moon RT . (2000). J. Cell Biol., 149, 249–254.
Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT and Hogg D . (2002). Nat. Genet., 31, 306–310.
Taylor MD, Mainprize TG and Rutka JT . (2000). Neurosurgery, 47, 888–901.
Taylor MD, Mainprize TG, Rutka JT, Becker L, Bayani J and Drake JM . (2001). Pediatr. Neurosurg., 35, 235–238.
Taylor MD, Perry J, Zlatescu MC, Stemmer-Rachamimov AO, Ang LC, Ino Y, Schwartz M, Becker LE, Louis DN and Cairncross JG . (1999). J. Neurosurg., 90, 946–950.
Thomas KR, Musci TS, Neumann PE and Capecchi MR . (1991). Cell, 67, 969–976.
van Es JH, Kirkpatrick C, van de Wetering M, Molenaar M, Miles A, Kuipers J, Destree O, Peifer M and Clevers H . (1999). Curr. Biol., 9, 105–108.
Vortmeyer AO, Stavrou T, Selby D, Li G, Weil RJ, Park WS, Moon YW, Chandra R, Goldstein AM and Zhuang Z . (1999). Cancer, 85, 2662–2667.
Wechsler-Reya RJ . (2003). Recent Prog. Horm. Res., 58, 227–248.
Wechsler-Reya RJ and Scott MP . (1999). Neuron., 22, 103–114.
Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ and Harper JW . (1999). Genes Dev., 13, 270–283.
Yokota N, Nishizawa S, Ohta S, Date H, Sugimura H, Namba H and Maekawa M . (2002). Int. J. Cancer, 101, 198–201.
Yong WH, Raffel C, von Deimling A and Louis DN . (1995). N. Engl. J. Med., 333, 524.
Zurawel RH, Chiappa SA, Allen C and Raffel C . (1998). Cancer Res., 58, 896–899.
Acknowledgements
MDT and TGM were supported by a fellowship from the Neurosurgery Research Education Foundation for this work. JTR is a career scientist of the CIHR. This work was completed with funds from the National Cancer Institute of Canada, Brainchild, the Wiley and Laurie Berman Fund for Brain Tumor Research.
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Taylor, M., Zhang, X., Liu, L. et al. Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling. Oncogene 23, 4577–4583 (2004). https://doi.org/10.1038/sj.onc.1207605
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DOI: https://doi.org/10.1038/sj.onc.1207605
