RNase L, a ubiquitous endoribonuclease in the IFN system, has been harnessed for the selective and catalytic cleavage of RNA targets that function in signal transduction and oncogenesis. Chimeric oligonucleotides (ODNs) are chemically-synthesized with a 2',5'-tetraadenylate activator (2- 5A) of RNase L covalently coupled to antisense ODNs. In essence, the 2- 5A portion of the chimera binds and activates RNase L while the antisense arm of the ODN binds the RNA target thus directing RNase L to degrade the RNA specifically. The goal of this project is to determine the molecular mechanism for the tumoricidal activity of 2-5A-antisense directed against human telomerase RNA (hTR) and thus better understand the role of telomerase in cancer and cell immortality. The hypothesis to be tested is that the tumoricidal effect of 2-5A-anti-hTR is due to inhibition of telomerase function which directly or indirectly triggers an apoptotic response. Different chemical forms of 2-5A-antisense will be designed to enhance biostability, hybridization affinity, cellular uptake and RNase L activation ability. We will probe the signaling events which lead to apoptosis in tumor cells treated with 2-5A-antisense to telomerase RNA. The contributions of caspases, STAT 1, and bcl-2 family members will be determined. Effects of 2-5A-antisense on global gene expression patterns, telomere length and chromosome stability will be determined. Because human but not murine RNase L is activated by 2-5A-antisense, an animal model for studying the anti-tumor effects of 2-5A-antisense against telomerase RNA will be generated by expressing human RNase L in RNase L-/- mice. The effects of IFN induction of RNase L will be determined in 2-5A-antisense treated cells and mice. Because 2-5A-anti- hTR is a potent experimental therapeutic agent for cancer, this proposal has the potential to make an impact on intractable forms of cancer, such as malignant glioma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA062220-08
Application #
6443849
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:

Showing the most recent 10 out of 253 publications