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SV-40 virus en asbest samen schadelijker bij muizen

30-05-2007 00:00

Een studie bij aan asbest blootgestelde muizen laat zien dat het sv-40 virus de ontwikkeling van mesothelioom stimuleert. De manier waarop is nog niet duidelijk. Het lijkt erop dat het virus de werking van het p-53 gen stopt: een gen dat de ontwikkeling van tumoren onderdrukt. Bron: Pietruska, J.R. & Kane, A.B., (2007). SV40 Oncoproteins Enhance Asbestos-Induced DNA Double-Strand Breaks and Abrogate Senescence in Murine Mesothelial Cells. Cancer Res, 67 (8), april 15, 3637-45.
Pietruska, J.R. & Kane, A.B., (2007). SV40 Oncoproteins Enhance Asbestos-Induced DNA Double-Strand Breaks and Abrogate Senescence in Murine Mesothelial Cells. Cancer Res, 67 (8), april 15, 3637-45.

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 .-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

B-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. [Cancer Res 2007.67(8):3637-45