Cooperative transformation of 32D cells by the combined expression of IRS-1 and V-Ha-Ras
| Autor: | Maria Giulia Rizzo, Barbara Cristofanelli, Anna Rita Morena, Alessandra Marchetti, Silvia Soddu, Michael Dews, Renato Baserga, Barbara Valentinis, Gianluca Bossi, Ada Sacchi |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Cell Survival Cellular differentiation Morpholines Gene Expression MAP Kinase Kinase Kinase 1 Mice Nude Oncogene Protein p21(ras) Protein Serine-Threonine Kinases mapk myelodysplastic syndrome pi3-k shc transformation Transfection Mice Phosphatidylinositol 3-Kinases Genetics Tumor Cells Cultured Animals Enzyme Inhibitors Molecular Biology Phosphoinositide-3 Kinase Inhibitors Flavonoids biology MEK inhibitor Cell Differentiation Phosphoproteins Phenotype Cell biology Androstadienes Enzyme Activation Cell Transformation Neoplastic Cell culture Chromones Mitogen-activated protein kinase Immunology biology.protein Insulin Receptor Substrate Proteins Rabbits Signal transduction Wortmannin |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 0950-9232 |
| Popis: | 32D cells expressing v-Ha-Ras fail to show a transformed phenotype. Since Ras requires an active IGF-1R for transformation of fibroblasts, we asked whether expression of IRS-1 or Shc (two of the major substrates of the IGF-1R) could co-operate with oncogenic Ras in transforming 32D cells. We find that IRS-1, but not Shc, in combination with v-Ha-Ras generates a fully transformed phenotype in 32D cells. 32D cells expressing both IRS-1 and v-Ha-Ras (32D/IRS1/Ras) survive and proliferate in the absence of IL-3, do not undergo granulocytic differentiation in the presence of G-CSF and form tumors in nu/nu and syngeneic mice. In contrast, 32D cells expressing singly IRS-1 or v-Ha-Ras exhibit only a block in differentiation capacity. Over-expression of Shc proteins, by itself, promotes differentiation of 32D cells. Concomitant expression of IRS-1 and v-Ha-Ras synergistically phosphorylates ERK-1 and ERK-2 whereas a MEK inhibitor rapidly induces death of 32D/IRS1/Ras transformed cells. Furthermore, transformed 32D/IRS1/Ras cells display high levels of PI3-K activation and undergo rapid apoptosis when exposed to PI3-K inhibitors. The data indicate that: (1) a fully transformed phenotype in 32D cells is generated when a block in differentiation (v-Ha-Ras) is coupled with another differentiation block (IRS-1); (2) PI3-K and MAPK activity are required for the survival of transformed cells; (3) the signals generated by IRS-1 and oncogenic Ras converge on ERK and PI3-K resulting in high levels of activation. |
| Databáze: | OpenAIRE |
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