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A more recent version of this article appeared on July 9, 2004 Originally published In Press as doi:10.1074/jbc.M313947200 on April 6, 2004
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Papers In Press, published online ahead of print May 6, 2004
J. Biol. Chem, 10.1074/jbc.M313947200
Submitted on December 19, 2003
Revised on March 31, 2004
Accepted on April 6, 2004

Mixed lineage kinase (MLK) 3-activated p38 MAP kinase mediates TGF-beta-induced apoptosis in hepatoma cells

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

Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892-5055

Corresponding Author: kims{at}mail.nih.gov

Although TGF-beta1 acts via the Smad signaling pathway to initiate de novo gene transcription, the TGF-beta1-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 N-terminal kinases (JNKs) are involved in TGF-beta1-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 kinase [DLK]) are expressed in FaO rat hepatoma cells and are likely to act between p38 and TGF-beta receptor kinase in death signaling. TGF-beta1 treatment leads to an increase in MLK3 activity. Overexpression of MLK3 enhances TGF-beta1 induced apoptotic death in FaO cells and Hep3B human hepatoma cells, while expression of the dominant-negative forms of MLK3 suppresses cell death induced by TGF-beta1. The dominant-negative forms of MLK1 and 2 also suppresses TGF-beta1-induced cell death. In MLK3 overexpressing cells, ERK, JNKs, and p38 MAP kinases were further activated in response to TGF-beta1 compared to the control cells. In contrast, overexpression of the dnMLK3 resulted in suppression of TGF-beta1-induced MAP kinase activation and TGF-beta1-induced caspase 3 activation. We also show that only the inhibition of the p38 pathway suppressed TGF-beta1-induced apoptosis. These observations support a role for MLKs in the TGF-beta1-induced cell death mechanism.


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