PMID- 12621046
OWN - NLM
STAT- MEDLINE
DCOM- 20030625
LR  - 20210206
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 20
DP  - 2003 May 16
TI  - Resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity and abnormal liver 
      development in mice carrying a mutation in the nuclear localization sequence of 
      the aryl hydrocarbon receptor.
PG  - 17767-74
AB  - The Ah receptor (AHR) mediates the metabolic adaptation to a number of planar 
      aromatic chemicals. Essential steps in this adaptive mechanism include AHR 
      binding of ligand in the cytosol, translocation of the receptor to the nucleus, 
      dimerization with the Ah receptor nuclear translocator, and binding of this 
      heterodimeric transcription factor to dioxin-responsive elements (DREs) upstream 
      of promoters that regulate the expression of genes involved in xenobiotic 
      metabolism. The AHR is also involved in other aspects of mammalian biology, such 
      as the toxicity of molecules like 2,3,7,8-tetrachlorodibenzo-p-dioxin as well as 
      regulation of normal liver development. In an effort to test whether these 
      additional AHR-mediated processes require a nuclear event, such as DRE binding, 
      we used homologous recombination to generate mice with a mutation in the AHR 
      nuclear localization/DRE binding domain. These Ahr(nls) mice were found to be 
      resistant to all 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxic responses that 
      we examined, including hepatomegaly, thymic involution, and cleft palate 
      formation. Moreover, aberrations in liver development observed in these mice were 
      identical to that observed in mice harboring a null allele at the Ahr locus. 
      Taken in sum, these data support a model where most, if not all, of AHR-regulated 
      biology requires nuclear localization.
FAU - Bunger, Maureen K
AU  - Bunger MK
AD  - McArdle Laboratory for Cancer Research and the Training Program in Environmental 
      Toxicology, University of Wisconsin Medical School, Madison, Wisconsin 53706, 
      USA.
FAU - Moran, Susan M
AU  - Moran SM
FAU - Glover, Edward
AU  - Glover E
FAU - Thomae, Tami L
AU  - Thomae TL
FAU - Lahvis, Garet P
AU  - Lahvis GP
FAU - Lin, Bernice C
AU  - Lin BC
FAU - Bradfield, Christopher A
AU  - Bradfield CA
LA  - eng
GR  - T32-ES07015/ES/NIEHS NIH HHS/United States
GR  - P01 CA022484/CA/NCI NIH HHS/United States
GR  - P01-CA14520/CA/NCI NIH HHS/United States
GR  - P01-CA22484/CA/NCI NIH HHS/United States
GR  - T32-CA09135/CA/NCI NIH HHS/United States
GR  - P30-CA07175/CA/NCI NIH HHS/United States
GR  - F32 ES005877-03/ES/NIEHS NIH HHS/United States
GR  - F32-ES05877/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.
DEP - 20030305
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Ligands)
RN  - 0 (Nuclear Localization Signals)
RN  - 0 (Oligonucleotides)
RN  - 0 (Polychlorinated Dibenzodioxins)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Teratogens)
SB  - IM
MH  - Alleles
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cell Nucleus/metabolism
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - *Drug Resistance
MH  - Fibroblasts/metabolism
MH  - Gene Targeting
MH  - Genetic Vectors
MH  - Ligands
MH  - Liver/*drug effects/embryology/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Models, Genetic
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Nuclear Localization Signals
MH  - Oligonucleotides/chemistry
MH  - Phenotype
MH  - Polychlorinated Dibenzodioxins/*toxicity
MH  - Precipitin Tests
MH  - Protein Structure, Tertiary
MH  - Receptors, Aryl Hydrocarbon/*genetics/metabolism
MH  - Recombinant Proteins/metabolism
MH  - Sequence Homology, Amino Acid
MH  - Teratogens/toxicity
MH  - Thymus Gland/drug effects/metabolism
MH  - Time Factors
EDAT- 2003/03/07 04:00
MHDA- 2003/06/26 05:00
CRDT- 2003/03/07 04:00
PHST- 2003/03/07 04:00 [pubmed]
PHST- 2003/06/26 05:00 [medline]
PHST- 2003/03/07 04:00 [entrez]
AID - S0021-9258(19)54861-X [pii]
AID - 10.1074/jbc.M209594200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 May 16;278(20):17767-74. doi: 10.1074/jbc.M209594200. Epub 2003 
      Mar 5.