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N-myc is an essential downstream effector of Shh signaling during both normal and neoplastic cerebellar growth.

Hatton, Beryl A and Knoepfler, Paul S and Kenney, Anna Marie and Rowitch, David H and de Alborán, Ignacio Moreno and Olson, James M and Eisenman, Robert N (2006) N-myc is an essential downstream effector of Shh signaling during both normal and neoplastic cerebellar growth. Cancer research, 66 (17). pp. 8655-8661. ISSN 1538-7445

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We examined the genetic requirements for the Myc family of oncogenes in normal Sonic hedgehog (Shh)-mediated cerebellar granule neuronal precursor (GNP) expansion and in Shh pathway-induced medulloblastoma formation. In GNP-enriched cultures derived from N-myc(Fl/Fl) and c-myc(Fl/Fl) mice, disruption of N-myc, but not c-myc, inhibited the proliferative response to Shh. Conditional deletion of c-myc revealed that, although it is necessary for the general regulation of brain growth, it is less important for cerebellar development and GNP expansion than N-myc. In vivo analysis of compound mutants carrying the conditional N-myc null and the activated Smoothened (ND2:SmoA1) alleles showed, that although granule cells expressing the ND2:SmoA1 transgene are present in the N-myc null cerebellum, no hyperproliferation or tumor formation was detected. Taken together, these findings provide in vivo evidence that N-myc acts downstream of Shh/Smo signaling during GNP proliferation and that N-myc is required for medulloblastoma genesis even in the presence of constitutively active signaling from the Shh pathway.

Item Type: Article
Additional Information: This article is freely available at the journal's website via the Article URL above.
DOI: 10.1158/0008-5472.CAN-06-1621
PubMed ID: 16951180
Grant Numbers: CA112350-01, CA114400-01, CA20525
Keywords or MeSH Headings: Animals; Cell Division; Cerebellar Neoplasms/genetics/pathology; Cerebellum/cytology/pathology; Child; Genes, myc; Hedgehog Proteins/physiology; Humans; Kinetics; Medulloblastoma/genetics/pathology; Mice; Mice, Knockout; Proto-Oncogene Proteins c-myc/deficiency/genetics; Signal Transduction;
Subjects: Cellular and Organismal Processes > Cell Physiology > Cell communication
Diseases > Solid tumors > Brain cancer
Cellular and Organismal Processes > Cell Physiology > Cell proliferation
Molecules > Genes > Oncogenes
Depositing User: Library Staff
Date Deposited: 17 Dec 2008 23:04
Last Modified: 24 May 2010 18:44

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