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J. Biol. Chem., Vol. 281, Issue 46, 34810-34815, November 17, 2006

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c-Jun NH₂-terminal Kinase Promotes Apoptosis by Down-regulating the Transcriptional Co-repressor CtBP^*

Su-Yan Wang, Mihail Iordanov, and Qinghong Zhang¹

From the Vollum Institute and Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239

Genetic knock out of the transcriptional co-repressor carboxyl-terminal-binding protein (CtBP) in mouse embryonic fibroblasts results in up-regulation of several genes involved in apoptosis. We predicted, therefore, that a propensity toward apoptosis might be regulated through changes in cellular CtBP levels. Previously, we have identified the homeodomain-interacting protein kinase 2 as such a regulator and demonstrated that HIPK2 activation causes Ser-422 phosphorylation and degradation of CtBP. In this study, we found that c-Jun NH₂-terminal kinase 1 activation triggered CtBP phosphorylation on Ser-422 and subsequent degradation, inducing p53-independent apoptosis in human lung cancer cells. JNK1 has previously been linked to UV-directed apoptosis. Expression of MKK7-JNK1 or exposure to UV irradiation reduced cellular levels of CtBP via a proteasome-mediated pathway. This effect was prevented by JNK1 deficiency. In addition, sustained activation of the JNK1 pathway by cisplatin similarly triggered CtBP degradation. These findings provide a novel target for chemotherapy in cancers lacking p53.

Received for publication, August 7, 2006 , and in revised form, September 18, 2006.

^* This work was supported by National Institutes of Health Grant 5K01CA096561 (to Q. Z.). 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: Vollum Inst., L-474, Oregon Health & Science University, 3181 S. W. Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-494-4676; Fax: 503-494-4353; E-mail: zhangq{at}ohsu.edu.

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