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J. Biol. Chem., Vol. 279, Issue 39, 40994-41003, September 24, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/39/40994    most recent M407369200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shin, J. Articles by Ahn, K. Search for Related Content PubMed PubMed Citation Articles by Shin, J. Articles by Ahn, K. Social Bookmarking                      What's this?

Promyelocytic Leukemia Is a Direct Inhibitor of SAPK2/p38 Mitogen-activated Protein Kinase^*

Jinwook Shin, Boyoun Park, Sunglim Cho, Sunray Lee, Youngkyun Kim, Seong-Ok Lee, Kwangmin Cho, Sungwook Lee, Bong-Suk Jin, Jin-Hyun Ahn, Eui-Ju Choi, and Kwangseog Ahn¶

From the College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea and the Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea

The promyelocytic leukemia gene (PML) encodes a growth/tumor suppressor protein that is essential for the induction of apoptosis in response to various apoptotic signals. The mechanism by which PML plays a role in the regulation of cell death is still unknown. In the current study, we demonstrate that PML negatively regulated the SAPK2/p38 signaling pathway by sequestering p38 from its upstream kinases, MKK3, MKK4, and MKK6, whereas PML did not affect the SAPK1/c-Jun NH₂-terminal kinase pathway. PML associated with p38 both in vitro and in vivo and the carboxyl terminus of PML mediated the interaction. In contrast to other studies of PML and PML-nuclear bodies (NB), our study shows that the formation of PML-NBs was not required for PML to suppress p38 activity because PML was still able to bind and inhibit p38 activity under the conditions in which PML-NBs were disrupted. In addition, we show that the promotion of Fas-induced cell death by PML correlated with the extent of p38 inhibition by PML, suggesting that PML might regulate apoptosis through manipulating SAPK2/p38 pathways. Our findings define a novel function of PML as a negative regulator of p38 kinase and provide further understanding on the mechanism of how PML induces multiple pathways of apoptosis.

Received for publication, July 1, 2004

^* This work was supported by a grant from the Molecular and Cellular BioDiscovery Research Program and Center for Functional Analysis of Human Genome Grant FG-03-01 from the Ministry of Science and Technology. 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: School of Biological Sciences, Seoul National University, Kwanak-gu, Shinlim-dong San 56-1, Seoul 151-742, Korea. Tel.: 82-2-880-6698; Fax: 82-2-872-1993; E-mail: ksahn3{at}hanmail.net.

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