Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells.
Phospholipase D (PLD) is an important signaling enzyme implicated in the control of many biological processes, including cell proliferation and survival. Despite the importance of the duration and amplitude of PLD signaling in carcinogenesis, mechanisms that regulate PLD expression remain poorly understood. In our study, we define the regulatory components of the machinery that specifies selective PLD1 induction via signals propagated through PLD activity. We demonstrate for the first time that establishment of a positive feedback loop that is dependent on enzymatic activity originating from both PLD1 and PLD2 isozymes enhances selective expression of PLD1, but not PLD2. Phosphatidic acid, the product of PLD activity, leads to an increase in the Ras-ERK/PI3K-NFκB signaling cascade and enhances binding of NFκB to the PLD1 promoter, consequently inducing selective PLD1 expression in SK-BR3 breast cancer cells. Moreover, selective PLD inhibitor suppressed epidermal growth factor-induced matrix metalloproteinase upregulation and invasion by inhibiting PLD1 expression. In conclusion, we propose that autoregulation of PLD activity might be coupled to induction of PLD1 expression, and thereby play a role in carcinogenesis.
Kang
Dong Woo
DW
Department of Molecular Biology, College of Natural Science, Busan, Republic of Korea.
Park
Mi Hee
MH
Lee
Young Jun
YJ
Kim
Hyung Sik
HS
Lindsley
Craig W
CW
Alex Brown
H
H
Min
Do Sik
do S
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology; D005260:Female; D006706:Homeostasis; D006801:Humans; D007124:Immunoenzyme Techniques; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010712:Phosphatidic Acids / Q000494:pharmacology; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; D010712:Phosphatidic Acids; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D048490:raf Kinases; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1; D018631:ras Proteins