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J. Biol. Chem., Vol. 282, Issue 2, 938-946, January 12, 2007

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A Novel c-Jun-dependent Signal Transduction Pathway Necessary for the Transcriptional Activation of Interferon Response Genes^*

Daniel J. Gough, Kanaga Sabapathy^¶, Enoch Yi-No Ko, Helen A. Arthur, Robert D. Schreiber^||, Joseph A. Trapani¹, Christopher J. P. Clarke²³, and Ricky W. Johnstone²⁴

From the Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, Australia, University of Melbourne, Parkville 3054, Victoria, Australia, ^¶National Cancer Centre, Hospital Drive, Singapore 169610, Republic of Singapore, and ^||Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110

The biological effects of interferon (IFN) are mediated by interferon-stimulated genes (ISGs), many of which are activated downstream of Janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling. Herein we have shown that IFN rapidly activated AP-1 DNA binding that required c-Jun but was independent of JAK1 and STAT1. IFN-induced c-Jun phosphorylation and AP-1 DNA binding required the MEK1/2 and ERK1/2 signaling pathways, whereas the JNK1/2 and p38 mitogen-activated protein kinase pathways were dispensable. The induction of several ISGs, including ifi-205 and iNOS, was impaired in IFN-treated c-Jun^–/– cells, but others, such as IP-10 and SOCS3, were unaffected, and chromatin immunoprecipitation demonstrated that c-Jun binds to the iNOS promoter following treatment with IFN. Thus, IFN induced JAK1- and STAT1-independent activation of the ERK mitogen-activated protein kinase pathway, phosphorylation of c-Jun, and activation of AP-1 DNA binding, which are important for the induction of a subset of ISGs. This represents a novel signal transduction pathway induced by IFN that proceeds in parallel with conventional JAK/STAT signaling to activate ISGs.

Received for publication, August 11, 2006 , and in revised form, November 9, 2006.

^* This work was supported by a grant from the National Health and Medical Research Council (NHMRC) of Australia and from the National Medical Research Council and Biomedical Research Council of Singapore (to K. S.). 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 Figs. S1–S5.

¹ A senior principal research fellow of the NHMRC.

² These authors are co-senior authors on this paper.

³ To whom correspondence may be addressed: Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, Victoria, Australia. Tel.: 61-3-9656-1657; Fax: 61-3-9656-1411; E-mail: chris.clarke{at}petermac.org. ⁴ A Pfizer Australia senior research fellow. To whom correspondence may be addressed: Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, Victoria, Australia. Tel.: 61-3-9656-3727; Fax: 61-3-9656-1411; E-mail: ricky.johnstone{at}petermac.org.

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