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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039360-22
Application #
6834646
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Cole, John S
Project Start
1984-07-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
22
Fiscal Year
2005
Total Cost
$335,975
Indirect Cost
Name
Oregon Health and Science University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Iordanov, M S; Ryabinina, O P; Schneider, P et al. (2005) Two mechanisms of caspase 9 processing in double-stranded RNA- and virus-triggered apoptosis. Apoptosis 10:153-66
Iordanov, Mihail S; Sundholm, Aaron J; Simpson, Eric L et al. (2005) Cell death-induced activation of epidermal growth factor receptor in keratinocytes: implications for restricting epidermal damage in dermatitis. J Invest Dermatol 125:134-42
Iordanov, Mihail S; Choi, Remy J; Ryabinina, Olga P et al. (2002) The UV (Ribotoxic) stress response of human keratinocytes involves the unexpected uncoupling of the Ras-extracellular signal-regulated kinase signaling cascade from the activated epidermal growth factor receptor. Mol Cell Biol 22:5380-94
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Iordanov, M S; Wong, J; Bell, J C et al. (2001) Activation of NF-kappaB by double-stranded RNA (dsRNA) in the absence of protein kinase R and RNase L demonstrates the existence of two separate dsRNA-triggered antiviral programs. Mol Cell Biol 21:61-72
Iordanov, M S; Ryabinina, O P; Wong, J et al. (2000) Molecular determinants of apoptosis induced by the cytotoxic ribonuclease onconase: evidence for cytotoxic mechanisms different from inhibition of protein synthesis. Cancer Res 60:1983-94
Iordanov, M S; Wong, J; Newton, D L et al. (2000) Differential requirement for the stress-activated protein kinase/c-Jun NH(2)-terminal kinase in RNAdamage-induced apoptosis in primary and in immortalized fibroblasts. Mol Cell Biol Res Commun 4:122-8
Iordanov, M S; Paranjape, J M; Zhou, A et al. (2000) Activation of p38 mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase by double-stranded RNA and encephalomyocarditis virus: involvement of RNase L, protein kinase R, and alternative pathways. Mol Cell Biol 20:617-27
Keller, D; Zeng, X; Li, X et al. (1999) The p38MAPK inhibitor SB203580 alleviates ultraviolet-induced phosphorylation at serine 389 but not serine 15 and activation of p53. Biochem Biophys Res Commun 261:464-71

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