Insulin receptor substrate 1 is an effector of sonic hedgehog mitogenic signaling in cerebellar neural precursors
| Autor: | Susana R. Parathath, Dane Ohlosson Campbell, Lori A. Mainwaring, Anna Marie Kenney, Africa Fernandez-L |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
endocrine system
Cell type animal structures medicine.medical_treatment Models Neurological Mitosis Biology Article Mice Downregulation and upregulation Cerebellum medicine Animals Hedgehog Proteins RNA Messenger Sonic hedgehog Cerebellar Neoplasms Molecular Biology Cells Cultured PI3K/AKT/mTOR pathway Cell Proliferation DNA Primers Neurons Base Sequence Effector Ribosomal Protein S6 Kinases Stem Cells TOR Serine-Threonine Kinases Growth factor Mice Mutant Strains Up-Regulation IRS1 Phosphotransferases (Alcohol Group Acceptor) embryonic structures Insulin Receptor Substrate Proteins Cancer research biology.protein Signal transduction Carrier Proteins Medulloblastoma Signal Transduction Developmental Biology |
| Zdroj: | Development. 135:3291-3300 |
| ISSN: | 1477-9129 0950-1991 |
| DOI: | 10.1242/dev.022871 |
| Popis: | Sonic hedgehog (SHH) and insulin-like growth factor (IGF) signaling are essential for development of many tissues and are implicated in medulloblastoma, the most common solid pediatric malignancy. Cerebellar granule neuron precursors (CGNPs), proposed cells-of-origin for specific classes of medulloblastomas, require SHH and IGF signaling for proliferation and survival during development of the cerebellum. We asked whether SHH regulates IGF pathway components in proliferating CGNPs. We report that SHH-treated CGNPs showed increased levels of insulin receptor substrate 1(IRS1) protein, which was also present in the germinal layer of the developing mouse cerebellum and in mouse SHH-induced medulloblastomas. Previous roles for IRS1, an oncogenic protein that is essential for IGF-mediated proliferation in other cell types, have not been described in SHH-mediated CGNP proliferation. We found that IRS1 overexpression can maintain CGNP proliferation in the absence of SHH. Furthermore, lentivirus-mediated knock down experiments have shown that IRS1 activity is required for CGNP proliferation in slice explants and dissociated cultures. Contrary to traditional models for SHH signaling that focus on gene transcription, SHH stimulation does not regulate Irs1 transcription but rather stabilizes IRS1 protein by interfering with mTOR-dependent IRS1 turnover and possibly affects Irs1 mRNA translation. Thus, we have identified IRS1 as a novel effector of SHH mitogenic signaling that may serve as a future target for medulloblastoma therapies. Our findings also indicate a previously unreported interaction between the SHH and mTOR pathways, and provide an example of a non-classical means for SHH-mediated protein regulation during development. |
| Databáze: | OpenAIRE |
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