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J. Biol. Chem., Vol. 283, Issue 7, 4094-4104, February 15, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/7/4094    most recent M707416200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kang, D. W. Articles by Min, D. S. Search for Related Content PubMed PubMed Citation Articles by Kang, D. W. Articles by Min, D. S. Social Bookmarking                      What's this?

Phorbol Ester Up-regulates Phospholipase D1 but Not Phospholipase D2 Expression through a PKC/Ras/ERK/NFB-dependent Pathway and Enhances Matrix Metalloproteinase-9 Secretion in Colon Cancer Cells^*

Dong Woo Kang, Mi Hee Park, Young Jun Lee, Hyung Sik Kim, Taeg Kyu Kwon^¶, Won-Sang Park^||, and Do Sik Min¹

From the Department of Molecular Biology, College of Natural Science, and College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea, the ^¶Department of Immunology, School of Medicine, Keimyung University, 194 Daegu 700-712, Republic of Korea, and the ^||Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea

Despite its importance in cell proliferation and tumorigenesis, very little is known about the molecular mechanism underlying the regulation of phospholipase D (PLD) expression. PLD isozymes are significantly co-overexpressed with cancer marker genes in colorectal carcinoma. Phorbol 12-myristate 13-acetate (PMA) treatment, as a mitogenic signal in colon cancer cells, selectively increases PLD1 expression in transcription and post-transcription. Moreover, experiments using intraperitoneal injection of PMA into mice showed selective PLD1 induction in the intestine and lung tissues, which suggests its physiological relevance in vivo. Therefore, we have undertaken a detailed analysis of the effects of PMA on the promoter activity of PLD genes. Protein kinase C inhibitors, but not a protein kinase A inhibitor, were found to suppress the up-regulation of PLD1 but not PLD2. Dominant-negative mutants of Ras, Raf, and MEK suppressed the induction and activity of PLD1. Moreover, depletion of the supposedly involved proteins reduced the endogenous PLD1 protein level. An important role for NFB as a downstream target of ERK in PMA-induced PLD1 induction was also demonstrated using the inhibitor, small interfering RNA, chromatin immunoprecipitation assay, and site-specific mutagenesis. Furthermore, inhibitors of these signaling proteins and depletion of PLD1 suppressed PMA-induced matrix metalloproteinase-9 secretion and PLD1 induction. In conclusion, we demonstrate for the first time that induction of PLD1 through a protein kinase C/Ras/ERK/NFB-dependent pathway is involved in the secretion of matrix metalloproteinase-9 in colorectal cancer cells.

Received for publication, September 4, 2007 , and in revised form, December 6, 2007.

^* This study was supported by the Nation R&D Program for Cancer Control, Republic of Korea, Grant 0620040. 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 supplemental Fig. S1.

¹ To whom correspondence should be addressed: Dept. of Molecular Biology, College of Natural Science, Pusan National University, 30 Jangjeon dong, Geumjeong gu, Busan 609-735, Republic of Korea. Tel: 82-51-510-3682; Fax: 82-51-513-9258; E-mail: minds{at}pusan.ac.kr.

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