Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice Journal Article
| Authors: | Rao, G.; Pedone, C. A.; Valle, L. D.; Reiss, K.; Holland, E. C.; Fults, D. W. |
| Article Title: | Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice |
| Abstract: | Medulloblastoma (MB) is a malignant brain tumor that arises in the cerebellum of children. Activation of the Sonic hedgehog/Patched (Shh/Ptc) signaling pathway in neural progenitor cells of the cerebellum induces MBs in mice. The incomplete penetrance of tumor formation in mice, coupled with the low frequency of mutations in Shh/ Ptc pathway genes in human tumors, suggests that other signaling molecules cooperate with Shh to enhance MB formation. We modeled the ability of insulin-like growth factor (IGF) signaling to induce MB using the RCAS/tv-a system, which allows postnatal gene transfer and expression in a cell-type-specific manner. We used RCAS retroviral vectors to target expression of Shh, IGF2, and activated Akt to nestin-expressing neural progenitors in the cerebella of newborn mice. The incidence of Shh-induced tumor formation (15%) was enhanced by coexpression with IGF2 (39%) and Akt (48%). Neither IGF2 nor Akt caused tumors when expressed independently. The induced tumors showed upregulated expression of insulin receptor substrate 1 and phosphorylated forms of IGF1 receptor and Akt, mimicking activated IGF signaling found in human MBs. These results indicate that combined activation of the Shh/Ptc and IGF signaling pathways is an important mechanism in MB pathogenesis. |
| Keywords: | signal transduction; protein kinase b; controlled study; protein expression; protein phosphorylation; gene mutation; proto-oncogene proteins; nonhuman; animal cell; mouse; animals; mice; animal tissue; cerebellum; gene expression; cell line; sonic hedgehog protein; animal experiment; hedgehog proteins; nerve tissue proteins; carcinogenesis; cell type; gene transfer; animalia; genetic vectors; stem cell; somatomedin c receptor; protein-serine-threonine kinases; medulloblastoma; newborn; proto-oncogene proteins c-akt; retrovirus vector; stem cells; upregulation; trans-activators; nestin; sonic hedgehog; nerve cell; cerebellar neoplasms; erinaceidae; intermediate filament proteins; somatomedin b; retroviridae; chickens; epicoccum; igf2; insulin-like growth factor ii; neural progenitors; insulin receptor substrate 1; unidentified retrovirus; humans; priority journal; article; rcas/tv-a |
| Journal Title: | Oncogene |
| Volume: | 23 |
| Issue: | 36 |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2004-08-01 |
| Start Page: | 6156 |
| End Page: | 6162 |
| Language: | English |
| DOI: | 10.1038/sj.onc.1207818 |
| PROVIDER: | scopus |
| PUBMED: | 15195141 |
| DOI/URL: | |
| Notes: | Oncogene -- Cited By (since 1996):143 -- Export Date: 16 June 2014 -- CODEN: ONCNE -- Source: Scopus |
