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J. Biol. Chem., Vol. 281, Issue 27, 18734-18745, July 7, 2006

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Human Gene Profiling in Response to the Active Protein Kinase, Interferon-induced Serine/threonine Protein Kinase (PKR), in Infected Cells

INVOLVEMENT OF THE TRANSCRIPTION FACTOR ATF-3 IN PKR-INDUCED APOPTOSIS^*

Susana Guerra¹, Luis A. López-Fernández, María Angel García², Angel Zaballos, and Mariano Esteban³

From the Departments of Molecular and Cellular Biology and Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Ciudad Universitaria de Cantoblanco, E-28049 Madrid, Spain

The interferon-induced serine/threonine protein kinase (PKR) has an essential role in cell survival and cell death after viral infection and under stress conditions, but the host genes involved in these processes are not well defined. We used human cDNA microarrays to identify, in infected cells, genes differentially expressed after PKR expression and analyzed the requirement of catalytic activity of the enzyme. To express PKR, we used vaccinia virus (VV) recombinants producing wild type PKR (VV-PKR) and the catalytically inactive mutant K296R (VV-PKR-K296R). Most regulated genes were classified according to biological function, including apoptosis, stress, defense, and immune response. Transcriptional changes detected by microarray analysis were confirmed for selected genes by quantitative real time reverse transcription PCR. A total of 111 genes were regulated specifically by PKR catalytic activity. Of these, 97 were up-regulated, and 14 were down-regulated. The ATF-3 transcription factor, involved in stress-induced -cell apoptosis, was up-regulated. Activation of endogenous PKR with a VV mutant lacking the viral protein E3L (VVE3L), a PKR inhibitor, triggered an increase in ATF-3 expression that was not observed in PKR^-/- cells. Using null cells for ATF-3 and for the p65 subunit of NF-B, we showed that induction of apoptosis by PKR at late times of infection was dependent on ATF-3 expression and regulated by NF-B activation. Here, we identified human genes selectively induced by expression of active PKR in infected cells and linked ATF-3 to a novel mechanism used by PKR to induce apoptosis.

Received for publication, November 7, 2005 , and in revised form, April 5, 2006.

^* This work was supported by European Union (EU) Spanish Research Grants BIO2000-0340-P4, BMC2002-03246, and QLK2002-00954 (to M. E). The Dept. of Immunology and Oncology was founded and is supported by Consejo Superior de Investigaciones Científicas and by Pfizer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2.

¹ Supported by a contract from the EU project on Vaccinia Vectors.

² Supported by the Ministry of Science and Technology of Spain.

³ To whom correspondence should be addressed: Dept. of Molecular and Cellular Biology, CentroNacionaldeBiotecnología,CSIC,CiudadUniversitariaCantoblanco,Madrid28049, Spain. Tel.: 34-91-585-4553; Fax: 34-91-585-4506; E-mail: mesteban{at}cnb.uam.es.

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