Cooperative action of germ-line mutations in decorin and p53 accelerates lymphoma tumorigenesis
| Autor: | Inge Eichstetter, Renato V. Iozzo, Bruno Calabretta, David J. McQuillan, Fatima Chakrani, Danilo Perrotti, Tomasz Skorski |
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| Rok vydání: | 1999 |
| Předmět: |
Decorin
Biology Lymphoma T-Cell medicine.disease_cause Cell Line Mice medicine Animals Epidermal growth factor receptor Germ-Line Mutation Thymic Lymphoma Mice Knockout Regulation of gene expression Extracellular Matrix Proteins Gene Expression Regulation Lymphoma T-Cell/pathology and genetics Multidisciplinary Kinase Neoplasms Experimental Biological Sciences medicine.disease Gene Expression Regulation Neoplastic carbohydrates (lipids) Cancer research biology.protein Proteoglycans Ectopic expression Tumor Suppressor Protein p53 Carcinogenesis Cell Division |
| Zdroj: | Proceedings of the National Academy of Sciences. 96:3092-3097 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Ectopic expression of decorin in a wide variety of transformed cells results in growth arrest and the inability to generate tumors in nude mice. This process is caused by a decorin-mediated activation of the epidermal growth factor receptor, which leads to a sustained induction of endogenous p21 WAF1/CIP1 (the cyclin-dependent kinase inhibitor p21) and growth arrest. However, mice harboring a targeted disruption of the decorin gene do not develop spontaneous tumors. To test the role of decorin in tumorigenesis, we generated mice lacking both decorin and p53, an established tumor-suppressor gene. Mice lacking both genes showed a faster rate of tumor development and succumbed almost uniformly to thymic lymphomas within 6 months [mean survival age (T 50 ) ∼4 months]. Mice harboring one decorin allele and no p53 gene developed the same spectrum of tumors as the double knockout animals, but had a survival rate similar to the p53 null animals (T 50 ∼ 6 months). Ectopic expression of decorin in thymic lymphoma cells isolated from double mutant animals markedly suppressed their colony-forming ability. When these lymphoma cells were cocultured with fibroblasts derived from either wild-type or decorin null embryos, the cells grew faster in the absence of decorin. Moreover, exogenous decorin proteoglycan or its protein core significantly retarded their growth in vitro . These results indicate that the lack of decorin is permissive for lymphoma tumorigenesis in a mouse model predisposed to cancer and suggest that germ-line mutations in decorin and p53 may cooperate in the transformation of lymphocytes and ultimately lead to a more aggressive phenotype by shortening the tumor latency. |
| Databáze: | OpenAIRE |
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