Dataset Information

Cyclin-dependent kinase activity is required for type I interferon production.

ABSTRACT: Recognition of nucleic acids results in the production of type I IFNs, which activate the JAK/STAT pathway and promote the expression of IFN-stimulated genes. In a search for modulators of this pathway, we discovered an unexpected requirement for cyclin-dependent kinases (CDK) in the production of type I IFN following nucleic acid sensing and virus infection. Inhibition of CDK activity or knockdown of CDK levels leads to a striking block in STAT activation and IFN-stimulated gene expression. CDKs are not required for the initial nucleic acid sensing leading to IFN-? mRNA induction, nor for the response to exogenous IFN-?/?, but are critical for IFN-? release into culture supernatants, suggesting a posttranscriptional role for CDKs in type I IFN production. In the absence of CDK activity, we demonstrate a translational block specific for IFN-?, in which IFN-? mRNA is removed from the actively translating polysomes, while the distribution of other cellular mRNAs or global translation rates are unaffected. Our findings reveal a critical role for CDKs in the translation of IFN-?.

SUBMITTER: Cingoz O

PROVIDER: S-EPMC5879699 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cyclin-dependent kinase activity is required for type I interferon production.

Cingöz Oya O Goff Stephen P SP

Proceedings of the National Academy of Sciences of the United States of America 20180305 13

Recognition of nucleic acids results in the production of type I IFNs, which activate the JAK/STAT pathway and promote the expression of IFN-stimulated genes. In a search for modulators of this pathway, we discovered an unexpected requirement for cyclin-dependent kinases (CDK) in the production of type I IFN following nucleic acid sensing and virus infection. Inhibition of CDK activity or knockdown of CDK levels leads to a striking block in STAT activation and IFN-stimulated gene expression. CDK ...[more]

PMID: 29507205

Similar Datasets

Project description:Novel treatments for glioblastoma, the most common malignant primary brain tumor, are urgently required. Type I interferons (IFN) are natural cytokines primarily involved in the defense against viral infections, which may also serve a role in the control of cancer, notably in the suppression of the cancer stem cell phenotype. TG02 is a novel orally available cyclin-dependent kinase 9 inhibitor which induces glioma cell apoptosis without profound caspase activation, which is currently explored in early clinical trials in newly diagnosed and recurrent glioblastoma. In the present study, human glioma-initiating cell line models were used to explore whether IFN-? modulates the anti-glioma activity of TG02. The present study employed immunoblotting to assess protein levels, several viability assays and gene silencing strategies to assess gene function. Pre-exposure to IFN-? sensitized human glioma models to a subsequent exposure to TG02. Combination treatment was associated with increased DEVD-amc cleaving caspase activity that was blocked by the anti-apoptotic protein, BCL2. However, BCL2 did not protect from the synergistic effects of IFN and TG02 on glioma cell growth. Furthermore, although IFN strongly induced pro-apoptotic XIAP-associated factor (XAF) expression, disrupting XAF expression did not abrogate the synergy with TG02. Consistent with that, caspase 3 gene silencing did not abrogate the effects of TG02 or IFN-? alone or in combination. Finally, it was observed that IFN-? may indeed modulate the effects of TG02 upstream in the signaling cascade since inhibition of RNA polymerase II phosphorylation, a direct readout of the pharmacodynamic activity of TG02, was facilitated when glioma cells were pre-exposed to IFN-?. In summary, these data suggest that type I IFN may be combined with TG02 to limit glioblastoma growth, but that the well characterized effects of IFN and TG02 on apoptotic signaling are dispensable for synergistic tumor growth inhibition. Instead, exploring how IFN signaling primes glioma cells for TG02-mediated direct target inhibition may help to design novel and effective pharmacological approaches to glioblastoma.

Dataset Information

Cyclin-dependent kinase activity is required for type I interferon production.

Publications

Cyclin-dependent kinase activity is required for type I interferon production.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets