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SV40 oncoproteins enhance asbestos-induced DNA double-strand breaks and abrogate senescence in murine mesothelial cells.
- Source :
-
Cancer research [Cancer Res] 2007 Apr 15; Vol. 67 (8), pp. 3637-45. - Publication Year :
- 2007
-
Abstract
- SV40 virus has emerged as a potential cofactor with asbestos in the development of diffuse malignant mesothelioma, but its precise role in the pathogenesis of this tumor is unclear. SV40 large T antigen is known to inactivate cellular proteins involved in DNA damage and senescence, including p53 and pRb. We hypothesize that SV40 oncoproteins will sensitize mesothelial cells to DNA damage induced by asbestos or chemotherapeutic agents. SV40 oncoprotein expression in murine mesothelial cell lines enhanced spontaneous and asbestos-induced double-strand breaks, indicated by gamma-H2AX foci, and potentiated micronucleus formation. Mesothelial cells exposed to asbestos or bleomycin for 96 h acquired senescent-like morphology and displayed elevated senescence-associated beta-galactosidase activity, reduced bromodeoxyuridine (BrdUrd) incorporation, and reduced colony formation. SV40 oncoprotein expression abrogated the senescent phenotype, and transfected cell lines showed an increase in both BrdUrd incorporation and colony formation after prolonged DNA damage. Murine mesothelial cell lines lacking wild-type p53 due to a point mutation or gene rearrangement also failed to senesce in response to asbestos or chemotherapeutic agents. In addition, stress-induced senescence in human mesothelial cell lines was impaired by SV40 oncoprotein expression (MeT-5A), p53 small interfering RNA, or spontaneous p53 mutation (REN). These studies suggest that exposure to DNA-damaging agents can induce senescence in both murine and human mesothelioma cell lines and suggest a major, although not exclusive, role for p53 in this response. SV40 virus may contribute to mesothelioma progression by impairing stress-induced senescence, in part through p53 inactivation, thereby favoring survival and proliferation of mesothelial cells that have sustained DNA damage.
- Subjects :
- Animals
Antigens, Polyomavirus Transforming biosynthesis
Antigens, Polyomavirus Transforming genetics
Cell Growth Processes physiology
Cell Line
Cellular Senescence
DNA drug effects
DNA metabolism
Epithelial Cells cytology
Epithelial Cells drug effects
Epithelial Cells physiology
Humans
Mice
Transfection
Tumor Suppressor Protein p53 deficiency
Tumor Suppressor Protein p53 metabolism
beta-Galactosidase metabolism
Antibiotics, Antineoplastic pharmacology
Antigens, Polyomavirus Transforming physiology
Asbestos pharmacology
Bleomycin pharmacology
DNA Damage
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 67
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 17440075
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-05-3727