Interferon-alpha (IFNalpha) is a multifunctional cytokine, which is clinically effective in the treatment of human malignancies, viral infections and auto-immune diseases. IFNalpha elicits pleiotropic biological effects by regulating gene expression through signals generated upon its binding to a surface receptor on target cells (IFNalphaR). The first cloned subunit of the IFNalphaR, IFNAR1, plays a decisive role as a IFN signal transducing subunit but does not directly bind IFNalpha. The IFNalpha-induced tyrosine phosphorylation of STAT transcription factors is crucial in activated protein kinase (ERK2) also contribute to IFNalpha action. Based on the applicant's recent studies, the hypothesis to be tested is that via the IFNalpha-induced binding of STAT3 to the IFNalphaR, STAT3 (a transcription factor regulation the acute phase response genes), couples IFNalphaR signaling to pathways involving PI-3 kinase (phosphatidylinositol-3' kinase, an upstream element in a serine kinase transduction cascade), NF-kappaB (nuclear factor-kappaB, a transcription factor for genes important in inflammation and preventing apoptosis), and serine kinases (PKC subspecies and ERK2).
In Specific Aim 1, how STAT3 acts as an adapter to couple IFNalpha signaling pathways will be characterized. To be determined is if STAT3 activation (specifically via the docking domain in STAT3 for the p85 subunit of PI-3 kinase) is required for IFNalpha-induced: PI-3 kinase activation, PKC activation, ERK2 activation, gene expression, anti-viral action, and the anti- proliferative action.
In Specific Aim 2, the role of PI-3 kinase arm of the STAT3-signaling pathway in IFNalpha action will be defined. The effect of expressing dominant negative and constitutively active PI-3 kinase constructs will be examined on IFNalpha-induced: serine phosphorylation of cellular substrates, PKC activation, ERK2 activation, DNA-binding activity, gene expression, anti-viral action, anti-proliferative action, and inhibition of programmed cell death.
In specific Aim 3, the role of the NF-kappaB component of the STAT3-signaling pathway in IFNalpha action will be defined. To be determine are the mechanism for NF-kappaB activation, the interaction of STAT3 with NF-kappaB proteins, and the role of NF-kappaB activation on IFNalpha-induced: gene expression, anti-viral activity, anti-proliferative activity, inhibition of programmed cell death. The overall goal of these studies to determine how the activation of STAT3, PI-3 kinase and NF-kappaB are linked, and to determine their roles in effecting IFN's biological actions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073753-03
Application #
6124542
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Mccarthy, Susan A
Project Start
1997-12-02
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
3
Fiscal Year
2000
Total Cost
$290,254
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pathology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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Balasubramanian, Sujata; Fan, Meiyun; Messmer-Blust, Angela F et al. (2011) The interferon-gamma-induced GTPase, mGBP-2, inhibits tumor necrosis factor alpha (TNF-alpha) induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-kappaB and Rac protein. J Biol Chem 286:20054-64
Pfeffer, Lawrence M (2011) The role of nuclear factor *B in the interferon response. J Interferon Cytokine Res 31:553-9
Yang, Chuan He; Fan, Meiyun; Slominski, Andrzej T et al. (2010) The role of constitutively activated STAT3 in B16 melanoma cells. Int J Interferon Cytokine Mediat Res 2010:1-7
Du, Ziyun; Fan, Meiyun; Kim, Jong-Gwan et al. (2009) Interferon-resistant Daudi cell line with a Stat2 defect is resistant to apoptosis induced by chemotherapeutic agents. J Biol Chem 284:27808-15
Yang, Chuan He; Murti, Aruna; Pfeffer, Susan R et al. (2008) The role of TRAF2 binding to the type I interferon receptor in alternative NF kappaB activation and antiviral response. J Biol Chem 283:14309-16
Wei, Lai; Fan, Meiyun; Xu, Lijing et al. (2008) Bioinformatic analysis reveals cRel as a regulator of a subset of interferon-stimulated genes. J Interferon Cytokine Res 28:541-51
Gharavi, Nima M; Alva, Jackelyn A; Mouillesseaux, Kevin P et al. (2007) Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo. J Biol Chem 282:31460-8
Du, Ziyun; Wei, Lai; Murti, Aruna et al. (2007) Non-conventional signal transduction by type 1 interferons: the NF-kappaB pathway. J Cell Biochem 102:1087-94
Dickson, Paxton V; Hamner, John B; Streck, Christian J et al. (2007) Continuous delivery of IFN-beta promotes sustained maturation of intratumoral vasculature. Mol Cancer Res 5:531-42

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