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J. Biol. Chem., Vol. 275, Issue 37, 28341-28344, September 15, 2000

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ACCELERATED PUBLICATION
Patched Target Igf2 Is Indispensable for the Formation of Medulloblastoma and Rhabdomyosarcoma^*

Heidi Hahn^§, Leszek Wojnowski^¶, Katja Specht, Roland Kappler, Julia Calzada-Wack, Diana Potter, Anne Zimmer^¶**, Ulrike Müller, Elenore Samson, Leticia Quintanilla-Martinez, and Andreas Zimmer^¶**

From the  Institute of Pathology, TUM Technical University of Munich/GSF Research Center of Environment and Health, Ingolstädter Landstrasse 1, 85758 Neuherberg, Federal Republic of Germany, the ^¶ Laboratory of Genetics, NIMH, National Institutes of Health, Bethesda, Maryland 20892, the  Veterinary Medicine and Resources Branch, NIMH, National Institutes of Health, Bethesda, Maryland 20892, the ^** Clinic for Psychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Federal Republic of Germany

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children (Dagher, R., and Helman, L. (1999) Oncologist 4, 34-44), whereas medulloblastoma, a highly malignant tumor of the cerebellum, accounts for 20% of childhood brain tumors (Goodrich, L. V., and Scott, M. P. (1998) Neuron 21, 1243-1257). Both tumors are associated with a deficiency in the tumor suppressor Patched (PTCH) in Gorlin syndrome (Gorlin, R. J. (1987) Medicine (Baltimore) 66, 98-113), and they are present in the corresponding murine models. RMS in Ptch mutant mice consistently contain elevated levels of the tumor growth-promoting insulin-like growth factor 2 (Igf2). We have investigated the mechanism of Igf2 overexpression and its significance in medulloblastoma and RMS tumorigenesis. Here we report that Igf2 is indispensable for the formation of medulloblastoma and RMS in Ptch mutants. Overexpression of Igf2 in RMS in these mice does not involve loss of imprinting, uniparental disomy, amplification of the Igf2 locus, or polyploidy. Since Igf2 is also overexpressed in non-tumor tissue deficient in Ptch, these observations suggest that Ptch regulates Igf2 levels through a transcriptional mechanism. They also identify Igf2 as a potential target for medulloblastoma and RMS.

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