SV40 and cell cycle perturbations in malignant mesothelioma.
Although epidemiological findings have established that exposure to asbestos fibers is the major cause of malignant mesothelioma (MM), recent studies have implicated simian virus 40 (SV40) in the etiology of some of these tumors. Cytogenetic and molecular genetic evidence suggests that multiple somatic genetic events are required for tumorigenic conversion of a mesothelial cell. As with many other types of cancer, in MM critical oncogenic events exert their action via perturbations of the cell cycle. Interactions between the retinoblastoma (Rb) family of proteins and oncoproteins encoded by SV40 lead to cell cycle alterations. Likewise, inhibition of the p53 tumor suppressor by SV40 can inactivate a crucial cell cycle checkpoint, thereby permitting cells to undergo mitosis regardless of the presence of DNA damage. Many MMs exhibit loss and/or inactivation of the tumor suppressors p16(INK4a)and p14(ARF), components of the pRb and p53 cell cycle regulatory pathways, respectively. Recent investigations have demonstrated that SV40 large T antigen, isolated from frozen biopsies of human MM specimens, binds to and inactivates various tumor suppressor gene products such as pRb and p53. In this review, we discuss how SV40-oncosuppressor interactions can lead to functional alterations of the pRb- and p53-dependent cell cycle regulatory pathways and thereby contribute to neoplastic transformation of human mesothelial cells.
Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. JR.Testa@fccc.edu
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JR
Testa
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A
Giordano
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D006801:Humans; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D018301:Neoplasms, Mesothelial / Q000378:metabolism / Q000821:virology*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D013539:Simian virus 40 / Q000502:physiology*; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D011506:Proteins; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53