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

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Affiliated Author(s)
권택규
Alternative Author(s)
Kwon, Taeg Kyu
Journal Title
Journal of Biological Chemistry
ISSN
0021-9258
Issued Date
2008
Abstract
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 NFκB 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/NFκB-dependent pathway is involved in the secretion of matrix metalloproteinase-9 in colorectal cancer cells.
Department
Dept. of Immunology (면역학)
Publisher
School of Medicine
Citation
Dong Woo Kang et al. (2008). Phorbol Ester Up-regulates Phospholipase D1 but Not Phospholipase D2 Expression through a PKC/Ras/ERK/ NF KB-dependent Pathway and Enhances Matrix Metalloproteinase-9 Secretion in Colon Cancer Cells. Journal of Biological Chemistry, 283(7), 4094–4104. doi: 10.1074/jbc.M707416200
Type
Article
ISSN
0021-9258
DOI
10.1074/jbc.M707416200
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/33952
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
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