Type I interferons include more than l0 subtypes of IFN-alpha, as well as IFN-beta, IFN-tau and IFN-omega. These related cytokines all signal through the IFN alpha/beta receptor, a complex composed of two transmembrane components (IFNAR-l/2) and two nonreceptor protein tyrosine kinases, TYK2 and JAK1. It has recently become clear that diverse signals can be generated by engagement of this receptor complex with its various ligands. Two distinctive outcomes of treatment with IFN-beta have been described: inducible transcription of a gene termed beta-R1, and assembly of a stable complex of IFN-beta with the two receptor chains. We propose that the induction of beta-Rl requires both common and unique signaling through the IFNAR-l/2 complex. This hypothesis is based on our preliminary results, which demonstrate that beta-RI transcription is dependent on all components needed to form the transcription factor ISGF3, but is atypically sensitive to phosphoinositol-3 kinase (PI3K) inhibitors and exhibits an unusual requirement for catalytically active TYK2. This research proposal addresses the hypothesis that 13-RI transcription depends on conformation-dependent signaling through the IFNAR-1/2 complex in response to IFN-beta as compared with IFN-alpha. This signaling pathway acts through catalytic TYK2 and PI3K, as well as ISGF3.
The specific aims are to: l) characterize IFN-beta signaling to the beta3-Rl promoter; 2) generate cells selectively unresponsive to IFN-beta and 3) determine gene expression selectively regulated by IFN-beta. Performance of these aims will provide insight into IFN-beta-specific signaling and help clarify the functional roles of accessory components, such as PI3K, in type I IFN response pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA062220-08
Application #
6443848
Study Section
Project Start
2001-04-01
Project End
2002-03-31
Budget Start
Budget End
Support Year
8
Fiscal Year
2001
Total Cost
$91,598
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Herjan, Tomasz; Hong, Lingzi; Bubenik, Jodi et al. (2018) IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling. Nat Immunol 19:354-365
Veleeparambil, Manoj; Poddar, Darshana; Abdulkhalek, Samar et al. (2018) Constitutively Bound EGFR-Mediated Tyrosine Phosphorylation of TLR9 Is Required for Its Ability To Signal. J Immunol 200:2809-2818
Nan, Jing; Wang, Yuxin; Yang, Jinbo et al. (2018) IRF9 and unphosphorylated STAT2 cooperate with NF-?B to drive IL6 expression. Proc Natl Acad Sci U S A 115:3906-3911
Sarvestani, Samaneh K; Signs, Steven A; Lefebvre, Veronique et al. (2018) Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids. Oncotarget 9:28717-28730
Cai, Gang; Zhu, Liang; Chen, Xing et al. (2018) TRAF4 binds to the juxtamembrane region of EGFR directly and promotes kinase activation. Proc Natl Acad Sci U S A 115:11531-11536
Zhou, Hao; Bulek, Katarzyna; Li, Xiao et al. (2017) IRAK2 directs stimulus-dependent nuclear export of inflammatory mRNAs. Elife 6:
Wang, Chenhui; Zhang, Cun-Jin; Martin, Bradley N et al. (2017) IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression. Nat Commun 8:15508
Wang, Yuxin; Nan, Jing; Willard, Belinda et al. (2017) Negative regulation of type I IFN signaling by phosphorylation of STAT2 on T387. EMBO J 36:202-212
Doherty, Mary R; Cheon, HyeonJoo; Junk, Damian J et al. (2017) Interferon-beta represses cancer stem cell properties in triple-negative breast cancer. Proc Natl Acad Sci U S A 114:13792-13797
Liu, Caini; Zhu, Liang; Fukuda, Koichi et al. (2017) The flavonoid cyanidin blocks binding of the cytokine interleukin-17A to the IL-17RA subunit to alleviate inflammation in vivo. Sci Signal 10:

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