PMID- 23639626
OWN - NLM
STAT- MEDLINE
DCOM- 20130820
LR  - 20161125
IS  - 1879-3185 (Electronic)
IS  - 0300-483X (Linking)
VI  - 309
DP  - 2013 Jul 5
TI  - TCDD induces the expression of insulin-like growth factor binding protein 4 in 5L 
      rat hepatoma cells: a cautionary tale of the use of this cell line in studies on 
      dioxin toxicity.
PG  - 107-16
LID - S0300-483X(13)00118-2 [pii]
LID - 10.1016/j.tox.2013.04.014 [doi]
AB  - Previous quantitative proteomic studies on the actions of 
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 5L rat hepatoma cells, a cell model 
      frequently used for investigating the mechanisms of TCDD toxicity, had indicated 
      that dioxin exposure reduced the abundance of numerous proteins which are 
      regulated at the level of protein synthesis initiation. In the present study, we 
      have analysed the mechanism mediating this inhibition. TCDD treatment of the 
      cells largely prevented the activation of eukaryotic translation initiation 
      factor 4E-binding protein 1, a regulator of translation initiation and substrate 
      of the mammalian target of rapamycin (mTOR). By "working upwards" from mTOR, we 
      observed that TCDD inhibited endogenous and IGF-I-induced AKT and ERK activation 
      by interfering with tyrosine phosphorylation of insulin receptor substrate 1. 
      This inhibition was mediated by a TCDD-induced secreted factor which was 
      identified as insulin-like growth factor binding protein 4 (IGFBP-4). The 
      induction of IGFBP-4 protein was dependent on a functional aryl hydrocarbon 
      receptor and was preceded by a rapid increase in the level of IGFBP-4 mRNA 
      indicating that IGFBP-4 is a previously unknown transcriptional target of TCDD in 
      5L cells. IGFBP-4 was not induced by TCDD in the parental cell line of 5L cells, 
      Fao, and in various closely related rat hepatoma cell lines as well as in other 
      unrelated cell types. Analysis of 5L cell chromosomes by multicolour spectral 
      karyotyping (SKY) revealed that the cells carry several hitherto uncharacterised 
      chromosomal translocations. The observations suggest that in 5L cells the Igfbp-4 
      gene may have got under the control of a promoter containing dioxin responsive 
      element(s) leading to the induction of IGFBP-4 by TCDD. These findings emphasise 
      a particular caution when interpreting and extrapolating results on the action 
      mechanisms of TCDD obtained in studies using 5L cells as a model system.
CI  - Copyright (c) 2013 Elsevier Ireland Ltd. All rights reserved.
FAU - Brandner, Stefanie
AU  - Brandner S
AD  - Helmholtz Zentrum Munchen, German Research Center for Environmental Health, 
      Institute of Molecular Toxicology and Pharmacology, Ingolstadter Landstr. 1, 
      85764 Neuherberg, Germany. brandner@helmholtz-muenchen.de
FAU - Eberhagen, Carola
AU  - Eberhagen C
FAU - Lichtmannegger, Josef
AU  - Lichtmannegger J
FAU - Hieber, Ludwig
AU  - Hieber L
FAU - Andrae, Ulrich
AU  - Andrae U
LA  - eng
PT  - Journal Article
DEP - 20130429
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - 0 (Dioxins)
RN  - 0 (Insulin-Like Growth Factor Binding Protein 4)
RN  - 0 (Polychlorinated Dibenzodioxins)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Dioxins/toxicity
MH  - *Gene Expression Regulation, Neoplastic/drug effects
MH  - Insulin-Like Growth Factor Binding Protein 4/*biosynthesis/genetics
MH  - Liver Neoplasms, Experimental/genetics/*metabolism
MH  - Polychlorinated Dibenzodioxins/*toxicity
MH  - Rats
EDAT- 2013/05/04 06:00
MHDA- 2013/08/21 06:00
CRDT- 2013/05/04 06:00
PHST- 2013/04/08 00:00 [received]
PHST- 2013/04/18 00:00 [revised]
PHST- 2013/04/19 00:00 [accepted]
PHST- 2013/05/04 06:00 [entrez]
PHST- 2013/05/04 06:00 [pubmed]
PHST- 2013/08/21 06:00 [medline]
AID - S0300-483X(13)00118-2 [pii]
AID - 10.1016/j.tox.2013.04.014 [doi]
PST - ppublish
SO  - Toxicology. 2013 Jul 5;309:107-16. doi: 10.1016/j.tox.2013.04.014. Epub 2013 Apr 
      29.