Endogenous and environmental events converge to activate intracellular cascades that ultimately decide whether cells will live or will undergo a program of cell death (apoptosis). In response to cellular damage, normal cells often undergo apoptosis to prevent the emergence of genetically altered cells that may develop into malignancies. Because the signaling cascades that control apoptosis are often found to be dysfunctional in cancer cells, it is thought that their dysfunction may contribute to the emergence of cancer. The NF-kappaB and MAPK/SAPK cascades are two of the regulatory pathways thought to control cell survival and apoptosis. The modulation of these cascades in response to viruses, and the consequent production of double-stranded RNA (dsRNA), are thought to play the major role in regulating the life-or-death decisions made by infected cells. In the field of cancer research, the study of virus-host cell interactions has revealed many cellular mechanisms whose dysfunction plays a role in carcinogenesis and tumor progression. In this proposal we seek to understand how viruses, and dsRNA in particular, modulate the NF-kappaB and MAPK/SAPK signaling cascades, and how these cascades control the pro- and anti-apoptotic pathways within cells. When viruses infect cells, the NF-kappaB and MAPK/SAPK cascades are thought to play a major role in controlling the life or death of these cells. DsRNA, which is produced by viruses in infected cells, is thought to be the major trigger that initiates apoptosis and the host cell's responses to viruses. We have employed this paradigm to investigate the cellular targets that sense the presence of dsRNA and the mechanisms by which they convey signals to activate the NF-kappaB and SAPK signaling cascades and apoptosis.
The aims of this proposal are: a) to clarify the role of the ribosome as a potential sensor and transducer of pro-apoptotic and survival signals in response to dsRNA; b) to elucidate the participation of MAPK and SAPK in regulating the pro- and anti-apoptotic signals in response to dsRNA; c) to elucidate the role of NF-kappaB in regulating the pro- and antiapoptotic signals in response to dsRNA; and d) to elucidate the dsRNA-modulated genes that are regulated by NF-kappaB and the NF-kappaB-regulated transcription factor Stat1.
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