Silencing of BNIP3 results from promoter methylation by DNA methyltransferase 1 induced by the mitogen-activated protein kinase pathway |
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| Authors: | Hyun-Jung An Hayyoung Lee Sang-Gi Paik |
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| Institution: | 1.Department of Biology, College of Biological Sciences and Biotechnology,Chungnam National University,Daejeon,Korea;2.Brain Korea 21 Daedeok R&D Innopolis Bio Brain Center, College of Biological Sciences and Biotechnology,Chungnam National University,Daejeon,Korea;3.Institute of Biotechnology, College of Biological Sciences and Biotechnology,Chungnam National University,Daejeon,Korea |
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| Abstract: | We have previously shown that Ras mediates NO-induced BNIP3 expression via the MEK-E RK-HIF-1 pathway i n mouse macrophages, and that NO-induced death results at least in part from the induction of
BNIP3. In the present study, we describe another aspect of Ras regulation of BNIP3 expression in pancreatic cancer cells.
Human BNIP3 promoter-driven luciferase activity was efficiently induced by activated Ras in AsPC-1, Miapaca-2, PK-1 and PANC-1
cells. However, expression of endogenous BNIP3 was not induced, and BNIP3 up-regulation by hypoxia was also inhibited. Treatment
of the cells with the DNMT inhibitor, 5-aza-2-deoxycytidine, restored BNIP3 induction, indicating that DNA methylation of
the BNIP3 promoter was responsible for the inhibition of BNIP3 induction. Furthermore, inhibition of the MEK pathway with
U0126 reduced DNMT1 expression, but not that of DNMT3a and 3b, and restored the hypoxia-inducibility of BNIP3, suggesting
that the DNA methylation of the BNIP3 promoter was mediated by DNMT1 via the MEK pathway. |
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| Keywords: | BNIP3 DNMT1 MEK methylation Ras |
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