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J. Biol. Chem., Vol. 282, Issue 1, 91-99, January 5, 2007

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Hyperactive Variants of p38 Induce, whereas Hyperactive Variants of p38 Suppress, Activating Protein 1-mediated Transcription^*

From the Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

The p38 family of kinases is a subgroup of the mitogen-activated protein kinase family. It is composed of four isoforms and is involved in critical biological processes as well as in inflammatory diseases. The exact unique role of each p38 isoform in these processes is not understood well. To approach this question we have been developing intrinsically active variants of p38s. Recently we described a series of mutants of the human p38, which were spontaneously active as recombinant proteins purified from Escherichia coli cells. We show here that some of these mutants are spontaneously active in several mammalian cells in culture. The spontaneous activity of some mutants is higher than the activity of the fully activated wild type counterpart. We further produced mutants of the other p38 isoforms and found that p38^D176A, p38^D179A, p38^D176A, and p38^F324S are spontaneously active in vivo. The active mutants are also spontaneously phosphorylated. To test whether the mutants actually fulfill downstream duties of p38 proteins, we tested their effect on activating protein 1(AP-1)-mediated transcription. Active mutants of p38 induced AP-1-driven reporter genes, as well as the c-jun and c-fos promoters. An active variant of p38 suppressed AP-1-mediated transcription. When active variants of p38 and p38 were co-expressed, AP-1 activity was not induced, showing that p38 is dominant over p38 with respect to AP-1 activation. Thus, intrinsically active variants that are spontaneously active in vivo have been obtained for all p38 isoforms. These variants have disclosed different effects of each isoform on AP-1 activity.

Received for publication, August 21, 2006 , and in revised form, October 25, 2006.

^* This work was supported by a grant from the Israeli Cancer Association and by Israel Science Foundation Grant 656/06. 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.

¹ To whom correspondence should be addressed. Tel.: 972-2-658-4718; Fax: 972-2-658-4910; E-mail: engelber{at}cc.huji.ac.il.

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