A transcriptional signaling pathway in the IFN system mediated by 2'-5'-oligoadenylate activation of RNase L.
Virus replication in higher vertebrates is restrained by IFNs that cause cells to transcribe genes encoding antiviral proteins, such as 2'-5' oligoadenylate synthetases. 2'-5' oligoadenylate synthetase is stimulated by dsRNA to produce 5'-phosphorylated, 2'-5'-linked oligoadenylates (2-5A), whose function is to activate RNase L. Although RNase L is required for a complete IFN antiviral response and mutations in the RNase L gene (RNASEL or HPC1) increase prostate cancer rates, it is unknown how 2-5A affects these biological endpoints through its receptor, RNase L. Presently, we show that 2-5A activation of RNase L produces a remarkable stimulation of transcription (>/=20-fold) for genes that suppress virus replication and prostate cancer. Unexpectedly, exposure of DU145 prostate cancer cells to physiologic levels of 2-5A (0.1 muM) induced approximately twice as many RNA species as it down-regulated. Among the 2-5A-induced genes are several IFN-stimulated genes, including IFN-inducible transcript 1/P56, IFN-inducible transcript 2/P54, IL-8, and IFN-stimulated gene 15. 2-5A also potently elevated RNA for macrophage inhibitory cytokine-1/nonsteroidal antiinflammatory drug-activated gene-1, a TGF-beta superfamily member implicated as an apoptotic suppressor of prostate cancer. Transcriptional signaling to the macrophage inhibitory cytokine-1/nonsteroidal antiinflammatory drug-activated gene-1 promoter by 2-5A was deficient in HeLa cells expressing a nuclease-dead mutant of RNase L and was dependent on the mitogen-activated protein kinases c-Jun N-terminal kinase and extracellular signal-regulated kinase, both of which were activated in response to 2-5A treatments. Because 2-5A and RNase L participate in defenses against viral infections and prostate cancer, our findings have implications for basic cellular mechanisms that control major pathogenic processes.
Malathi
Krishnamurthy
K
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Paranjape
Jayashree M
JM
Bulanova
Elena
E
Shim
Minsub
M
Guenther-Johnson
Jeanna M
JM
Faber
Pieter W
PW
Eling
Thomas E
TE
Williams
Bryan R G
BR
Silverman
Robert H
RH
D000227:Adenine Nucleotides / Q000378:metabolism* / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008156:Luciferases; D008297:Male; D046228:Microarray Analysis; D009154:Mutation / Q000235:genetics; D009843:Oligoribonucleotides / Q000378:metabolism* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology*
D000227:Adenine Nucleotides; D016207:Cytokines; D009843:Oligoribonucleotides; C023505:2',5'-oligoadenylate; D008156:Luciferases; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease