Transgenic mice harboring the early genome from the human neurotropic JC virus, JCV, develop massive abdominal tumors of neural crest origin during 6-8 months after birth and succumb to death a few weeks later. The viral early protein, T-antigen, which possesses the ability to transform cells of neural origin, is highly expressed in the tumor cells. Immunoblot analysis of protein extract from tumor tissue shows high level expression of the tumor suppressor protein, p53, in complex with T-antigen. Expression of p21, a downstream target for p53, which controls cell cycle progression by regulating the activity of cyclins and their associated kinases during the G1 phase, is extremely low in the tumor cells. Whereas the level of expression and activity of cyclin D1 and its associated kinase, cdk6, was modest in tumor cells, both cyclin A and E, and their kinase partners, cdk2 and cdk4, were highly expressed and exhibited significant kinase activity. The retinoblastoma gene product, pRb, which upon phosphorylation by cyclins:cdk induces rapid cell proliferation, was found in the phosphorylated state in tumor cell extracts, and was detected in association with JCV T-antigen. The transcription factor, E2F-1, which dissociates from the pRb-E2F-1 complex and stimulates S phase-specific genes upon phosphorylation of pRb and/or complexation of pRb with the viral transforming protein, was highly expressed in tumor cells. Accordingly, high level expression of the E2F-1-responsive gene, proliferating cell nuclear antigen (PCNA), was detected in the tumor cells. These observations suggest a potential regulating pathway that, upon expression of JCV T-antigen, induces formation and progression of tumors of neural origin in a whole animal system.
The presence of the outer membrane protein TraT, encoded by plasmid R6-5, reduces the sensitivity of Escherichia coli cells to phagocytosis by macrophages. This effect is independent of the bacterial capsule and is more evident in the presence of adsorbed normal human serum. The property of inhibiting phagocytosis is specifically abolished by anti-TraT protein antiserum and anti-TraT immunoglobulin G but not by Fab fragments. These results indicate that the TraT protein is a passive inhibitor of phagocytosis. Inhibition of phagocytosis is produced because the TraT protein antagonizes opsonization by complement, such that C3 deposition is reduced and altered in distribution.Phagocytosis and the bacteriostatic and bactericidal properties of the serum constitute the first line of defense against invasive bacterial infections. The antibacterial activity of blood is effective in eliminating most normally encountered transient bacteremias and is the result of a constellation of specific (e.g., antibodies) and nonspecific (e.g., complement, iron-binding proteins) factors (7,16).The ability of bacteria to avoid host defenses and become invasive rests largely in cell surface components which are important in the preliminary steps of the infective process and crucial in determining its outcome (35). The role of surface components such as capsules, peptidoglycan, proteins, pili, and 0-antigens in increasing the virulence of bacteria is well documented (34). Although most of these are encoded by genetic determinants located on the chromosome, recent reports testify to the importance of plasmidencoded gene product modifications to the cell surface, which alter bacterial virulence (13-15, 31, 33, 34).The Escherichia coli plasmid R6-5 carries a gene specifying resistance to the antibacterial activity of serum (31). This determinant, which has been identified as traT, is one of the genes of the tra operon, the genetic unit conferring conjugative ability upon the bacterial cell (1, 31). The traT gene directs the synthesis of a highly exposed outer membrane protein, which mediates resistance to serum. Since phagocytosis, the other main line of defense against invasive bacterial infections, involves complement, we explored the possibility that the TraT protein may confer upon bacteria the ability to resist phagocytosis. In this communication, we show that this is the case and that the protein interferes mainly with opsonization by the alternative pathway of complement by restricting and altering the pattern of C3 deposition. MATERIALS AND METHODSBacterial strains and plasmids. Bacterial strains and plasmids are listed in Table 1. Plasmid DNA, isolated by standard procedures, was introduced into bacterial strains by transformation or conjugation (45). Strains were stored at -20°C in 60% glycerol. Molecular cloning procedures. Restriction endonuclease * Corresponding author.cleavage of plasmid DNA, ligation reactions, transformations, screening, and analysis by agarose gel electrophoresis were performed as described (45,46). Media. ...
Nitroxides are antioxidant compounds that have been shown to provide radioprotection in vivo and in vitro. Radioprotection in vivo is limited by toxicity, which appears to be neurologic in nature. To further evaluate the toxicity of these compounds, three representative nitroxides, Tempol, Tempamine, and Tempo, were examined in slices of guinea pig hippocampus. Each nitroxide increased the population spike and caused potentiation of excitatory postsynaptic potential--spike coupling. Repetitive activity and epileptiform activity were observed at the highest concentrations of Tempo and Tempamine. Tempol was the least toxic compound in this system, followed by Tempamine and Tempo. Additional studies are necessary to further define the effects of nitroxides on the central nervous system and to develop strategies to mitigate these effects.
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