Understanding the molecular basis of interferon-alpha (IFNalpha) action is an important goal when one considers IFN's therapeutic potential in cancer, viral hepatitis, and multiple sclerosis, as well as its role as a model for understanding cytokine signal transduction. IFNalpha elicits its biological actions by regulating gene expression through the tyrosine phosphorylation and activation of members of the STAT (signal transducers and activators of transcription) protein family. The applicant found that STAT3, a transcription factor for acute phase response genes, is a critical element in IFN signaling and induction of IFN's biological actions. In addition, it was also found that IFN promotes cell survival by activating NF-kB (nuclear factor-kB) through a serine kinase-dependent pathway involving PI-3K (phosphatidylinositol-3' kinase) and Akt, as well as STAT3. Based on these findings, the general hypothesis to be tested is that the IFNalpha receptor integrates signaling pathways involving STAT3, PI-3K and NF-kB.
In Specific Aim 1, the role of STAT3 as a transcription factor and an adapter protein for PI-3K will be defined. The proposed studies will determine which specific amino acid residues in STAT3 undergo IFN-dependent phosphorylation, the relationship of these phosphorylation events to the biologic actions of IFN, and which IFN-responsive genes are STAT3- regulated.
In Specific Aim 2, the role of NF-kB in IFNa action will be defined. The proposed studies will define the relationship between PI-3K/Akt-mediated phosphorylation events and the anti-apoptotic action of IFN, the roles of TRAFs (TNF receptor-associated factors) and NIK (NF-kB-inducing kinase) in IFNinduced NF-kB activation, the role of NF-kB in gene induction by IFN, and the role of the IkB kinase complex in IFN promoted NF-kB activation and cell survival. Despite advances made on the IFNalpha signaling pathway, the mechanisms that underlie the induction of the different biological actions of IFNalpha remain poorly understood. This proposal focuses on characterizing the molecular basis of signaling pathways as they relate to IFN action on cell proliferation and survival.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA073753-06
Application #
6572560
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Mccarthy, Susan A
Project Start
1997-12-02
Project End
2007-11-30
Budget Start
2003-01-22
Budget End
2003-12-31
Support Year
6
Fiscal Year
2003
Total Cost
$303,306
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
Pfeffer, Susan R; Fan, Meiyun; Du, Ziyun et al. (2017) Unphosphorylated STAT3 regulates the antiproliferative, antiviral, and gene-inducing actions of type I interferons. Biochem Biophys Res Commun 490:739-745
Pfeffer, Lawrence M (2011) The role of nuclear factor *B in the interferon response. J Interferon Cytokine Res 31:553-9
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
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
Yang, Chuan He; Wei, Lai; Pfeffer, Susan R et al. (2007) Identification of CXCL11 as a STAT3-dependent gene induced by IFN. J Immunol 178:986-92
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

Showing the most recent 10 out of 28 publications