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J. Biol. Chem., Vol. 279, Issue 28, 29478-29484, July 9, 2004

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Mixed Lineage Kinase 3 (MLK3)-activated p38 MAP Kinase Mediates Transforming Growth Factor--induced Apoptosis in Hepatoma Cells^*

Ki-Yong Kim, Byung-Chul Kim, Zhiheng Xu¶, and Seong-Jin Kim||

From the Laboratory of Cell Regulation and Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892, the College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Korea, and the ^¶Department of Pathology and Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, New York 10032

Although transforming growth factor 1 (TGF-1) acts via the Smad signaling pathway to initiate de novo gene transcription, the TGF-1-induced MAPK kinase activation that is involved in the regulation of apoptosis is less well understood. Even though the p38 MAP kinase and c-Jun NH₂-terminal kinases (JNKs) are involved in TGF-1-induced cell death in hepatoma cells, the upstream mediators of these kinases remain to be defined. We show here that the members of the mixed lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper-bearing kinase (DLK)) are expressed in FaO rat hepatoma cells and are likely to act between p38 and TGF- receptor kinase in death signaling. TGF-1 treatment leads to an increase in MLK3 activity. Overexpression of MLK3 enhances TGF-1-induced apoptotic death in FaO cells and Hep3B human hepatoma cells, whereas expression of the dominant-negative forms of MLK3 suppresses cell death induced by TGF-1. The dominant-negative forms of MLK1 and -2 also suppress TGF-1-induced cell death. In MLK3-overexpressing cells, ERK, JNKs, and p38 MAP kinases were further activated in response to TGF-1 compared with the control cells. In contrast, overexpression of the dominant-negative MLK3 resulted in suppression of TGF-1-induced MAP kinase activation and TGF-1-induced caspase-3 activation. We also show that only the inhibition of the p38 pathway suppressed TGF-1-induced apoptosis. These observations support a role for MLKs in the TGF-1-induced cell death mechanism.

Received for publication, December 19, 2003 , and in revised form, March 31, 2004.

^* 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.

^|| To whom correspondence should be addressed. Tel.: 301-496-8350; Fax: 301-496-8395; E-mail: kims{at}mail.nih.gov.

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