Tumor necrosis factor a (TNF-a) is wellcharacterized for its necrotic action against tumor cells; however, it has been increasingly associated with an apoptosis-inducing potential on target cells. While the signaling events and the actual cytolytic mechanism(s) for both TNFca-induced necrosis and apoptosis remain to be fully elucidated, we report here on (i) the ability of TNF-a to induce apoptosis in the promonocytic U937 cells, (ii) the discovery of a cross-talk between the TNF-ai and the interferon signaling pathways, and (iii) the pivotal role of interferon-inducible, double-stranded RNA-activated protein kinase (PKR) in the induction of apoptosis by TNF-a. Our data from microscopy studies, trypan blue exclusion staining, and apoptotic DNA ladder electrophoresis revealed that a subclone derived from U937 and carrying a PKR antisense expression vector was resistant to TNF-ai-induced apoptosis. Further, TNF-a initiated a generalized RNA degradation process in which the participation of PKR was required. Finally, the PKR gene is a candidate "death gene" since overexpression of this gene could bring about apoptosis in U937 cells.
Despite what is known about the early signaling events in tumor necrosis factor (TNF) ␣-induced apoptosis, characterization of the downstream events remains largely undefined. It is now known that a crosstalk exists between the interferon and TNF-␣ pathways. This linkage allows recruitment of the cell proliferation suppressor PKR (dsRNA-dependent protein kinase) from the interferon pathway to play a pivotal role in TNF-␣-induced apoptosis. In this study, we took advantage of the differential TNF-␣ susceptibilities of human promonocytic U937 subclones, deficient in or overexpressing PKR, to further characterize the role of PKR in apoptosis. By reverse transcription-polymerase chain reaction, we demonstrated that TNF-␣ transiently induces the tumor suppressor p53 in U937 cells. This p53 induction lags behind the TNF-␣ induction of PKR by 1 h. By cell viability determination, ultrastructural studies, apoptotic DNA laddering, and antisense techniques, it was shown that inhibition of p53 expression in PKRoverexpressing U937 cells abrogates the TNF-␣-induced apoptosis in these cells. Conversely, overexpressing wild type p53 in PKR-deficient U937 cells confers the susceptibility of these cells to TNF-␣-induced apoptosis. This latter result indicates that p53 induction is an event downstream of TNF-␣-induced up-regulation of PKR, thereby further establishing the critical role of p53 in TNF-␣-induced apoptosis in U937 cells. PKR-overexpressing U937 cells were found to possess a constitutively higher level of p53, which partly explains why these cells spontaneously undergo apoptosis even without TNF-␣ treatment. Finally, a model is presented on the interplay between PKR and p53 in effecting TNF-␣-induced apoptosis in U937 cells.
Persistent infections by viruses such as HIV-1 and hepatitis B virus can pose long-term health hazards. Because establishment of persistent infections involves close interactions and adjustments in both host and virus, it would be informative to establish a paradigm with which a normally cytolytic viral infection can be easily converted to persistent infection, so that the different stages in developing persistent infection can be examined. Such a model system is described in this paper. Highly cytolytic encephalomyocarditis virus (EMCV) infection was shifted to persistent infection as a result of repressed expression of the double-stranded RNAdependent protein kinase (PKR) in the promonocytic U937 cells.
Because of the apoptogenic potential of PKR, a deficiency of PKR resulted in a delay in virus-induced apoptosis in EMCV-infected U937 cells, allowing the eventual establishment of persistent EMCV infection in these cells (U9K-AV2). That this was a bona fide persistent infection was demonstrated by the ability of infected cells to propagate as long-term virus-shedding cultures
Abstract-This study introduces the notion of 2-D and 3-D Phase Projection in our search for a simple and elegant solution to further reduce noise during InSAR post-processing steps with multiple baselines. Projection is a powerful tool to reduce noise in a system of more than two satellites. It does so by noting that the geometry of the satellite configuration restricts the range of values over which the wrapped phases can assume. Projection in general reduces noise in the system by utilizing the information provided by the configuration of the satellites to reduce the set of allowed phase points, thereby improving the robustness of the system in the presence of noise. Our results show that, for most cases, whether with the extremely small baseline distance or non-integer baseline ratios, using 3-D Projection gives better height inversion results.
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