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J. Biol. Chem., Vol. 281, Issue 45, 34475-34483, November 10, 2006

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Induction of Transcriptionally Active Jun Proteins Regulates Drug-induced Senescence^*

Orli Yogev, Shira Anzi, Kazushi Inoue, and Eitan Shaulian¹

From the Department of Experimental Medicine and Cancer Research, Hebrew University Medical School, Hadassah Ein Kerem, Jerusalem 91120, Israel and the Departments of Pathology/Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157

The drug hydroxyurea (HU) is used for cancer therapy and treatment of sickle cell anemia. It inhibits cell cycle progression by blocking DNA synthesis and drives cells to undergo apoptosis or enter senescence. We demonstrate here that HU induces the expression of two AP-1 proteins, c-Jun and JunB, which exert antagonistic effects on the cell cycle. Moreover, the induction of c-Jun is observed following treatment with two other drugs that inhibit the cell cycle in S phase, aphidicolin and camptothecin. The induction of c-Jun, which promotes cell cycle progression, up-regulates expression of cyclin D after exposure of cells to HU. Deficiency in c-jun prevents elevation of cyclin D expression and extends entrance into HU-induced senescence but also renders cells more resistant to HU-dependent apoptosis. The induction of c-Jun is independent of JNK activity, and additionally, of c-Jun autoregulatory activity but is inhibited upon inhibition of protein kinase C activity. Therefore, we suggest that c-Jun activity prevents drug-induced senescence. Conversely, the JunB target gene, tumor suppressor p16^INK4a, a cyclin-dependent kinase inhibitor essential for the induction of drug-induced senescence, is also up-regulated by HU in a JunB-dependent manner. Constitutive expression of JunB up-regulates p16^INK4a and increases the sensitivity of mouse fibroblasts to drug-induced-senescence. Thus, we suggest that in contrast to c-Jun, JunB drives cells to enter HU-dependent senescence. The effect of HU treatment, which regulates the intricate web of AP-1 transcription, depends on the balance between c-Jun and JunB activities.

Received for publication, March 27, 2006 , and in revised form, September 6, 2006.

^* This work is supported by a grant from the Israel Academy of Sciences. 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 two supplemental figures.

¹ To whom correspondence should be addressed. Tel.: 972-2-6757617; Fax: 972-2-6414583; E-mail: eshaulian{at}md.huji.ac.il.

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