Gadd45β is a pro-survival factor associated with stress-resistant tumors
| Autor: | A Engelmann, G W Bornkamm, Wolfgang Deppert, C Stocking, Daniel Speidel |
|---|---|
| Jazyk: | němčina |
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Lymphoma B-Cell Tumor suppressor gene Survival Mice SCID Biology medicine.disease_cause Mice Mice Inbred NOD Genetics medicine Animals Molecular Biology B-cell lymphoma MYC p53 Bcl-x(L) retroviral insertional mutagenesis stress-resistance medicine.disease Antigens Differentiation Lymphoma Transplantation Mice Inbred C57BL Disease Models Animal Oxidative Stress Tumor progression Immunology Cancer research NIH 3T3 Cells Syngenic GADD45B Carcinogenesis Ex vivo |
| Zdroj: | Oncogene 27, 1429-1438 (2008) |
| Popis: | Tumors that acquire resistance against death stimuli constitute a severe problem in the context of cancer therapy. To determine genetic alterations that favor the development of stress-resistant tumors in vivo, we took advantage of polyclonal tumors generated after retroviral infection of newborn Elambda-MYC mice, in which the retroviral integration acts as a mutagen to enhance tumor progression. Tumor cells were cultivated ex vivo and exposed to gamma-irradiation prior to their transplantation into syngenic recipients, thereby providing a strong selective pressure for pro-survival mutations. Secondary tumors developing from stress-resistant tumor stem cells were analysed for retroviral integration sites to reveal candidate genes whose dysregulation confer survival. In addition to the gene encoding the antiapoptotic Bcl-x(L) protein, we identified the gadd45b locus to be a novel common integration site in these tumors, leading to enhanced expression. In accord with a thus far undocumented role of Gadd45beta in tumorigenesis, we showed that NIH3T3 cells overexpressing Gadd45beta form tumors in NOD/SCID mice. Interestingly and differently to other known 'classical' antiapoptotic factors, high Gadd45beta levels did not protect against MYC-, UV- or gamma-irradiation-induced apoptosis, but conferred a strong and specific survival advantage to serum withdrawal. |
| Databáze: | OpenAIRE |
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