期刊
PLOS PATHOGENS
卷 7, 期 12, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1002405
关键词
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资金
- Helsinki Biomedical Graduate School
- European Commission [FP7-268301, LSHG-CT-2006-037900]
- Fondation pour la Recherche Medicale
- Swiss National Fund [3100A0-114001]
- Academy of Finland for the Center of Excellence in Translational Genome-Scale Biology
- Finnish Cancer Foundation
- Sigrid Juselius Foundation
- University of Helsinki Foundations
- European Union [LSHC-CT-2005-018704]
- DFG [SFB 576, HA1754-6]
- BMBF [01GS0801]
- MRC [G0501453]
- European Research Council (ERC) [260767]
- CNRS
- Ligue Nationale contre le Cancer
- European Research Council (ERC) [260767] Funding Source: European Research Council (ERC)
- Medical Research Council [G0501453] Funding Source: researchfish
- MRC [G0501453] Funding Source: UKRI
Kaposi's sarcoma herpesvirus (KSHV) encodes a cluster of twelve micro (mi)RNAs, which are abundantly expressed during both latent and lytic infection. Previous studies reported that KSHV is able to inhibit apoptosis during latent infection; we thus tested the involvement of viral miRNAs in this process. We found that both HEK293 epithelial cells and DG75 cells stably expressing KSHV miRNAs were protected from apoptosis. Potential cellular targets that were significantly down-regulated upon KSHV miRNAs expression were identified by microarray profiling. Among them, we validated by luciferase reporter assays, quantitative PCR and western blotting caspase 3 (Casp3), a critical factor for the control of apoptosis. Using site-directed mutagenesis, we found that three KSHV miRNAs, miR-K12-1, 3 and 4-3p, were responsible for the targeting of Casp3. Specific inhibition of these miRNAs in KSHV-infected cells resulted in increased expression levels of endogenous Casp3 and enhanced apoptosis. Altogether, our results suggest that KSHV miRNAs directly participate in the previously reported inhibition of apoptosis by the virus, and are thus likely to play a role in KSHV-induced oncogenesis.
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