Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2
| Autor: | James W. Freeman, William E. Strodel, Martin L. Adamo, Daniel T De Armond, Prakash Nair |
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| Rok vydání: | 2001 |
| Předmět: |
MAPK/ERK pathway
Transcriptional Activation Cancer Research medicine.medical_specialty Cell Survival medicine.medical_treatment RNA Stability Apoptosis Biology Culture Media Serum-Free Receptor IGF Type 1 Insulin-like growth factor Phosphatidylinositol 3-Kinases Internal medicine Genetics medicine Tumor Cells Cultured Humans RNA Messenger RNA Neoplasm Insulin-Like Growth Factor I Growth Substances Promoter Regions Genetic Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Cell growth Growth factor Cell cycle Cell biology Gene Expression Regulation Neoplastic Pancreatic Neoplasms Endocrinology Signal transduction Mitogen-Activated Protein Kinases Cell Division Signal Transduction |
| Zdroj: | Oncogene. 20(57) |
| ISSN: | 0950-9232 |
| Popis: | In the present study we investigated the mechanisms responsible for and the biological consequences of the constitutive activation of the insulin-like growth factor-1 receptor (IGF-1R) in the MIA PaCa-2 cells. An aberrant increase in the expression and activation of the IGF-1R was observed during the transition of growth states from exponential to quiescent. The increase in IGF-1R expression is preceded by an increase in IGF-1R mRNA transcript and is associated with an increase in the IGF-1R promoter activity. Inhibition of de novo transcription by actinomycin D increased the stability of IGF-1R mRNA in exponentially growing cells, thereby increasing the expression of IGF-1R to a level similar to that seen in quiescent cells. Increased IGF-1R signaling mediated the growth factor independence of quiescent MIA PaCa-2 cells through the constitutive activation of mitogen-activated protein kinase (MAPK). Exogenous IGF-1 increased cell proliferation and activated MAPK and AKT signaling pathways. The resistance of cells to apoptosis by IGF-1R signaling was mediated through MAPK and phosphatidylinositol 3-kinase (PI3K) pathways and a yet unidentified pathway(s). Thus, aberrant regulation of IGF-1R signaling is required for resistance to apoptosis and growth factor independence of MIA PaCa-2 cells. This likely protects cells from unfavorable conditions and allows cells to rapidly re-enter the cell cycle when conditions are favorable. |
| Databáze: | OpenAIRE |
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