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Phospholipase D Prevents Etoposide-Induced Apoptosis by Inhibiting the Expression of Early Growth Response-1 and Phosphatase and Tensin Homologue Deleted on Chromosome 10

¹ Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, South Korea; ² Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Ansan, South Korea; ³ Department of Immunology, School of Medicine, Keimyung University, Daegu, South Korea; ⁴ Department of Life Science, Daejin University, Kyeongggido, South Korea; and ⁵ Department of Biology, College of Sciences, Yonsei University, Seoul, South Korea

Requests for reprints: Do Sik Min, Department of Molecular Biology, College of Natural Science, Pusan National University, 30 Jangjeon-dong, Geumjeong-gu, 609-735 Busan, South Korea. Phone: 82-51-510-3682; Fax: 82-51-513-9258; E-mail: minds{at}pusan.ac.kr.

Phospholipase D (PLD) has emerged as a critical regulator of cell proliferation and survival signaling. We show for the first time that elevated expression of PLD isozymes attenuates expression of the tumor suppressors early growth response-1 (Egr-1) and the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor and apoptosis during etoposide treatment. When formation of phosphatidic acid was inhibited by overexpression of catalytically inactive PLD during etoposide treatment, expression of Egr-1 and PTEN and the apoptotic effect of etoposide were not inhibited. This suggests that PLD inhibits expression of these tumor suppressors and inhibits apoptosis. Deletion of a specific Egr-1-binding site present in the PTEN promoter blocked etoposide-induced PTEN activity and elevated expression of PLD decreased the sensitivity to apoptosis induced by ectopic expression of Egr-1. Etoposide-induced activation of Akt was potentiated by overexpression of PLD and PLD-stimulated suppression of Egr-1 was blocked by inhibition of phosphatidylinositol 3-kinase/Akt survival pathway at the both transcriptional and posttranscriptional levels. These results show that survival signals generated by PLD attenuate expression of Egr-1 by activation of phosphatidylinositol 3-kinase signaling pathway and induction of PTEN by Egr-1, which confers resistance to apoptosis. (Cancer Res 2006; 66(2): 784-93)

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