TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells
| Autor: | Martha R. Stampfer, Charlene E. Kan, Mark W. Jackson, James Graham, David Danielpour, Rocky Cipriano |
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| Rok vydání: | 2011 |
| Předmět: |
Cell Cycle Proteins
Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Biology Malignant transformation Transforming Growth Factor beta Humans Mammary Glands Human Cells Cultured Cellular Senescence Cell Proliferation Gene knockdown Multidisciplinary Cell growth Tumor Suppressor Proteins Epithelial Cells Transforming growth factor beta Biological Sciences Cell biology DNA-Binding Proteins Checkpoint Kinase 2 Cell Transformation Neoplastic ras Proteins Cancer research biology.protein Ectopic expression Tumor Suppressor Protein p53 Signal transduction Cell aging Signal Transduction Transforming growth factor |
| Zdroj: | Proceedings of the National Academy of Sciences. 108:8668-8673 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1015022108 |
| Popis: | Oncogene-induced senescence (OIS), the proliferative arrest engaged in response to persistent oncogene activation, serves as an important tumor-suppressive barrier. We show here that finite lifespan human mammary epithelial cells (HMEC) undergo a p16/RB- and p53-independent OIS in response to oncogenic RAS that requires TGF-β signaling. Suppression of TGF-β signaling by expression of a dominant-negative TGF-β type II receptor, use of a TGF-β type I receptor inhibitor, or ectopic expression of MYC permitted continued proliferation upon RAS expression. Surprisingly, unlike fibroblasts, shRNA-mediated knockdown of ATM or CHK2 was unable to prevent RAS-mediated OIS, arguing that the DNA damage response is not required for OIS in HMEC. Abrogation of TGF-β signaling not only allowed HMEC lacking p53 to tolerate oncogenic RAS but also conferred the capacity for anchorage-independent growth. Thus, the OIS engaged after dysregulated RAS expression provides an early barrier to malignant progression and is mediated by TGF-β receptor activation in HMEC. Understanding the mechanisms that initiate and maintain OIS in epithelial cells may provide a foundation for future therapies aimed at reengaging this proliferative barrier as a cancer therapy. |
| Databáze: | OpenAIRE |
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