PMID- 14764592
OWN - NLM
STAT- MEDLINE
DCOM- 20040722
LR  - 20210206
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 279
IP  - 16
DP  - 2004 Apr 16
TI  - Patent ductus venosus and dioxin resistance in mice harboring a hypomorphic Arnt 
      allele.
PG  - 16326-31
AB  - The Ah receptor nuclear translocator (ARNT) is the dimeric partner of 
      hypoxia-inducible factors and thus plays a pivotal role in cellular adaptation to 
      low oxygen environments. ARNT is also a dimeric partner for the Ah receptor 
      (AHR), and this complex is essential in regulating the adaptive metabolic 
      response to polycyclic aromatic hydrocarbons. Because of the essential role of 
      ARNT in hypoxia-driven developmental events, it has been difficult to study the 
      physiological significance of AHR.ARNT heterodimers in vivo. To address this 
      issue, we developed a hypomorphic Arnt allele that displayed normal development 
      and allowed the examination of the role of ARNT in AHR biology. In this regard, 
      the AHR is also known to mediate two additional biological processes: the 
      toxicological response to compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin 
      (dioxin) and the developmental closure of a fetal vascular structure known as the 
      ductus venosus. Although the mechanism of the adaptive pathway has been well 
      described, the mechanism of AHR-mediated signal transduction in the toxic and 
      developmental pathways is not well understood. Liver perfusion studies 
      demonstrated that ARNT hypomorphs have a patent ductus venosus, identical to that 
      observed in the Ahr null mice. Parallel dioxin toxicity studies demonstrated that 
      the ARNT hypomorphs exhibited resistance to the end points of dioxin exposure. 
      Moreover, we observed that toxicity could be segregated from the classical 
      adaptive responses such as P4501A induction. Taken in sum, these experiments 
      demonstrate that ARNT is an essential component of AHR developmental signaling 
      and shed light on the mechanism of dioxin toxicity.
FAU - Walisser, Jacqueline A
AU  - Walisser JA
AD  - McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, 
      Madison, Wisconsin 53706, USA.
FAU - Bunger, Maureen K
AU  - Bunger MK
FAU - Glover, Edward
AU  - Glover E
FAU - Harstad, Eric B
AU  - Harstad EB
FAU - Bradfield, Christopher A
AU  - Bradfield CA
LA  - eng
GR  - P01 CA022484/CA/NCI NIH HHS/United States
GR  - CA014520/CA/NCI NIH HHS/United States
GR  - R01 ES006883/ES/NIEHS NIH HHS/United States
GR  - CA022484/CA/NCI NIH HHS/United States
GR  - ES006881/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 - 20040205
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Arnt protein, mouse)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Dioxins)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (Transcription Factors)
RN  - 138391-32-9 (Aryl Hydrocarbon Receptor Nuclear Translocator)
SB  - IM
MH  - Alleles
MH  - Animals
MH  - Aryl Hydrocarbon Receptor Nuclear Translocator
MH  - *DNA-Binding Proteins
MH  - Dioxins/*toxicity
MH  - Drug Resistance/*genetics
MH  - Ductus Arteriosus, Patent/*genetics/metabolism
MH  - Mice
MH  - Receptors, Aryl Hydrocarbon/*genetics/metabolism
MH  - Signal Transduction/genetics
MH  - Transcription Factors/*genetics/metabolism
EDAT- 2004/02/07 05:00
MHDA- 2004/07/23 05:00
CRDT- 2004/02/07 05:00
PHST- 2004/02/07 05:00 [pubmed]
PHST- 2004/07/23 05:00 [medline]
PHST- 2004/02/07 05:00 [entrez]
AID - S0021-9258(20)88357-4 [pii]
AID - 10.1074/jbc.M400784200 [doi]
PST - ppublish
SO  - J Biol Chem. 2004 Apr 16;279(16):16326-31. doi: 10.1074/jbc.M400784200. Epub 2004 
      Feb 5.