PMID- 11391531
OWN - NLM
STAT- MEDLINE
DCOM- 20010628
LR  - 20231213
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 33
IP  - 6
DP  - 2001 Jun
TI  - Induction of Mdr1b expression by tumor necrosis factor-alpha in rat liver cells 
      is independent of p53 but requires NF-kappaB signaling.
PG  - 1425-31
AB  - The multidrug resistance protein Mdr1b in rats is up-regulated 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 IkappaB to inhibit pathways 
      downstream of the TNF receptor. Further, the proteasome inhibitor MG-132 was 
      used, which prevents the breakdown of IkappaB. 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.
FAU - Ros, J E
AU  - Ros JE
AD  - Groningen University Institute for Drug Exploration (GUIDE), Division of 
      Gastroenterology and Hepatology, Department of Internal Medicine, Groningen, the 
      Netherlands. j.e.ros@med.rug.nl
FAU - Schuetz, J D
AU  - Schuetz JD
FAU - Geuken, M
AU  - Geuken M
FAU - Streetz, K
AU  - Streetz K
FAU - Moshage, H
AU  - Moshage H
FAU - Kuipers, F
AU  - Kuipers F
FAU - Manns, M P
AU  - Manns MP
FAU - Jansen, P L
AU  - Jansen PL
FAU - Trautwein, C
AU  - Trautwein C
FAU - Muller, M
AU  - Muller M
LA  - eng
GR  - ES05851/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Tumor Suppressor Protein p53)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B/*genetics
MH  - Animals
MH  - Binding Sites/physiology
MH  - Carcinoma, Hepatocellular/genetics/pathology
MH  - Gene Expression Regulation/*physiology
MH  - Hepatocytes/physiology
MH  - I-kappa B Proteins/pharmacology
MH  - Liver/*physiology
MH  - Liver Neoplasms/genetics/pathology
MH  - NF-kappa B/*physiology
MH  - Promoter Regions, Genetic/physiology
MH  - Rats
MH  - Signal Transduction/*physiology
MH  - Transfection
MH  - Tumor Cells, Cultured
MH  - Tumor Necrosis Factor-alpha/*physiology
MH  - Tumor Suppressor Protein p53/*physiology
MH  - ATP-Binding Cassette Sub-Family B Member 4
EDAT- 2001/06/08 10:00
MHDA- 2001/06/29 10:01
CRDT- 2001/06/08 10:00
PHST- 2001/06/08 10:00 [pubmed]
PHST- 2001/06/29 10:01 [medline]
PHST- 2001/06/08 10:00 [entrez]
AID - S0270913901985581 [pii]
AID - 10.1053/jhep.2001.24667 [doi]
PST - ppublish
SO  - Hepatology. 2001 Jun;33(6):1425-31. doi: 10.1053/jhep.2001.24667.