Phospholipase D prevents etoposide-induced apoptosis by inhibiting the expression of early growth response-1 and phosphatase and tensin homologue deleted on chromosome 10.
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.
Kim
Joommo
J
Department of Molecular Biology, College of Natural Science, Pusan National University, 30 Jangleon-dong, Geumjeong-gu, 609-735 Busan, South Korea.
Lee
Young Han
YH
Kwon
Taeg Kyu
TK
Chang
Jong-Soo
JS
Chung
Kwang Chul
KC
Min
Do Sik
DS
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis*; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts; D006801:Humans; D007527:Isoenzymes; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D010739:Phospholipase D / Q000378:metabolism*; D015398:Signal Transduction
D000972:Antineoplastic Agents, Phytogenic; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D007527:Isoenzymes; D005047:Etoposide; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D010739:Phospholipase D