Induction of Mdr1b expression by tumor necrosis factor-α in rat liver cells is independent of p53 but requires NF-κB signaling
Induction of Mdr1b expression by tumor necrosis factor-α in rat liver cells is independent of p53 but requires NF-κB signaling
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DOI：
10.1053/jhep.2001.24667
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发表时间：
2001-06-01
期刊：
影响因子：
13.5
通讯作者：
Müller, M
中科院分区：
文献类型：
--
作者：
Ros, JE;Schuetz, JD;Müller, M
The multidrug resistance protein Mdr1b in rats is upregulated during liver regeneration after partial hepatectomy or after endotoxin treatment. We hypothesize that up-regulation of Mdr1b in these models is TNF-alpha -dependent. The mechanism of Mdr1b activation by TNF-alpha is unknown as TNF-alpha can signal through various pathways, including NF-kappaB and p53, transcription factors for which binding sites in the Mdr1b promoter have been identified. We aimed to elucidate the mechanism of up-regulation of Mdr1b by TNF-alpha, We selectively used constructs expressing dominant negative Fas-associated death domain protein (FADD), TNF receptor associated factor-2 (TRAF2) or I kappaB to inhibit pathways downstream of the TNF receptor. Further, the proteasome inhibitor MG-132 was used, which prevents the breakdown of I kappaB, We show a critical role for NF-kappaB in activation of Mdr1b gene expression both in primary rat hepatocytes and in rat hepatoma H-4-II-E cells, Because p53 is up-regulated by TNF-alpha in an NF-kappaB-dependent manner and the Mdr1b promoter contains a p53 binding site, we used liver cells expressing a dominant negative p53 to show that TNF-alpha up-regulation of Mdr1b is independent of functional p53, Using transient transfection assays, we show that Mdr1b up-regulation correlates with activation of the promoter. Mutation of the NF-kappaB site in the Mdr1b promoter prevents its induction by TNF-alpha. In conclusion our results show that activation of the rat Mdr1b gene by TNF-alpha is a result of NF-kappaB signaling and independent of p53.
