Interferons (IFNs) are members of a large family of extracellular proteins that mediate anti-tumor, immunomodulatory, anti-viral and anti-microbial actions. It is now clear that paradigms for intracellular signaling, developed using the IFN systems as models, are broadly applicable to many other molecules that, individually and in combination, regulate cell growth, differentiation, and inflammation. Study of the signaling events that mediate the diverse biological effects of IFNs has identified families of gene products that collectively transduce the signals not only from IFNs but also from many other stimuli. The work supported by this program project grant has led to significant contributions in developing this body of information, particularly through the application of forward genetics in mammalian cells. The overall theme of the renewal application focuses on the diverse mechanisms through which a relatively limited set of gene products generates the highly diverse array of biologic responses necessary to prevent the development and/or spread of cancer. The specific experimental targets include proteins that mediate the immediate signals in response to IFNs and other cytokines, including novel activities of JAKs and STATs, signaling molecules that are not JAKs or STATs, and downstream effectors responsible for biological outcomes. The experiments will utilize genetic, biochemical and molecular biological strategies to determine the functions of and interactions between individual protein targets. Project 1 will investigate signaling in response to TNF- alpha, study stimulus-independent activities of STAT1 and continue to explore new routes of IFN action that control the expression of the proto- oncogene, c-myc. In Project 2, the roles of cytosolic phospholipase A2, the double stranded RNA-dependent protein kinase PKR, and the protein tyrosine phosphatase SHP-1 in cytokine signaling will be further elaborated. Project 3 will be focused upon a navel signaling pathway responsible for IFNbeta-specific responses. Project 4 will expand upon the exciting finding that the IFN-inducible RNAse L system can be used to destroy tumors cells selectively by targeting the degradation of the RNA component of telomerase, which is necessary for immortalization of cancer cells. Project 5 will address the roles of dsRNA binding proteins in the control of IFN-inducible gene expression. Project 6 will define the molecular events associated with the inhibitory control of IFN-inducible gene expression by the anti-inflammatory cytokine IL-4. In sum, these interrelated and cooperative activities will further our knowledge of several signaling pathways that are important in cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA062220-07
Application #
6172171
Study Section
Subcommittee G - Education (NCI)
Program Officer
Mufson, R Allan
Project Start
1994-08-15
Project End
2004-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
7
Fiscal Year
2000
Total Cost
$1,916,971
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:

Showing the most recent 10 out of 253 publications