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Review
. 2014 Aug 15;289(33):22575-22582.
doi: 10.1074/jbc.R114.569822. Epub 2014 Jul 2.

Functional regulation of phospholipase D expression in cancer and inflammation

Dong Woo Kang  1 , Kang-Yell Choi  2 , Do Sik Min  3
Affiliations
Review

Functional regulation of phospholipase D expression in cancer and inflammation

Dong Woo Kang et al. J Biol Chem. .

Abstract

Phospholipase D (PLD) regulates downstream effectors by generating phosphatidic acid. Growing links of dysregulation of PLD to human disease have spurred interest in therapeutics that target its function. Aberrant PLD expression has been identified in multiple facets of complex pathological states, including cancer and inflammatory diseases. Thus, it is important to understand how the signaling network of PLD expression is regulated and contributes to progression of these diseases. Interestingly, small molecule PLD inhibitors can suppress PLD expression as well as enzymatic activity of PLD and have been shown to be effective in pathological mice models, suggesting the potential for use of PLD inhibitors as therapeutics against cancer and inflammation. Here, we summarize recent scientific developments regarding the regulation of PLD expression and its role in cancer and inflammatory processes.

Keywords: Cancer; Gene Expression; Gene Regulation; Inflammation; Phospholipase D; Phospholipase D Inhibitor; Therapeutic Drugs.

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Figures

FIGURE 1.
FIGURE 1.
Dynamics of differential regulation of PLD expression in cancer progression. Growth factor, mitogen, H. pylori infection, and Wnt signaling differentially express PLD isozymes via distinct signaling pathways or through different transcription factors depending on the physiological status of cells or cell type. TBE, TCF binding element.
FIGURE 2.
FIGURE 2.
Role of proinflammatory cytokine-induced PLD expression in chronic inflammation. A, proinflammatory cytokines selectively induce PLD1 expression via NFκB and ATF2. PLD1-derived PA promotes the binding of NFκB or HIF-1α to the promoters of its target genes and then increases the expression of proinflammatory mediators, migration, and angiogenic factors. However, PA suppresses the expression of cell cycle arrest genes via inhibition of FoxO3a transactivation. Moreover, PLD1 promotes osteoclastogenesis via up-regulation of RANKL expression in rheumatoid synovial fibroblasts stimulated by IL-15. Ultimately, up-regulation of PLD1 by proinflammatory cytokines can induce the pathogenesis of chronic inflammation. HRE, hypoxia-responsive element. B, during the early stages of inflammation, activation of leukocytes by MCP-1 induces the binding of Rac2 to PLD2 in the cytosol and then stimulates chemotaxis. During sustained inflammation, PLD2 expression is repressed by unknown mechanisms involving Rac and Sp1, and migration of the immune cells is suppressed. Prolonged immobilization of leukocytes by PLD2 repression can induce pathological stages of chronic inflammation. TBE, TCF binding element.
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References

    1. Hammond S. M., Altshuller Y. M., Sung T. C., Rudge S. A., Rose K., Engebrecht J., Morris A. J., Frohman M. A. (1995) Human ADP-ribosylation factor-activated phosphatidylcholine-specific phospholipase D defines a new and highly conserved gene family. J. Biol. Chem. 270, 29640–29643 - PubMed
    1. Colley W. C., Sung T. C., Roll R., Jenco J., Hammond S. M., Altshuller Y., Bar-Sagi D., Morris A. J., Frohman M. A. (1997) Phospholipase D2, a distinct phospholipase D isoform with novel regulatory properties that provokes cytoskeletal reorganization. Curr. Biol. 7, 191–201 - PubMed
    1. Balkwill F., Mantovani A. (2001) Inflammation and cancer: back to Virchow? Lancet 357, 539–545 - PubMed
    1. Kuper H., Adami H. O., Trichopoulos D. (2000) Infections as a major preventable cause of human cancer. J. Intern. Med. 248, 171–183 - PubMed
    1. Oliveira T. G., Chan R. B., Tian H., Laredo M., Shui G., Staniszewski A., Zhang H., Wang L., Kim T. W., Duff K. E., Wenk M. R., Arancio O., Di Paolo G. (2010) Phospholipase D2 ablation ameliorates Alzheimer's disease-linked synaptic dysfunction and cognitive deficits. J. Neurosci. 30, 16419–16428 - PMC - PubMed

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