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Molecular and Cellular Biology, April 2001, p. 2838-2846, Vol. 21, No. 8
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.8.2838-2846.2001
The Peptide Near the C Terminus Regulates Receptor CAR Nuclear
Translocation Induced by Xenochemicals in Mouse Liver
Igor
Zelko,
Tatsuya
Sueyoshi,
Takeshi
Kawamoto,
Rick
Moore, and
Masahiko
Negishi*
Pharmacogenetics Section, Laboratory of Reproductive and
Developmental Toxicology, National Institute of Environmental
Health Sciences, National Institutes of Health, Research Triangle Park,
North Carolina 27709
Received 20 October 2000/Returned for modification 3 January
2001/Accepted 16 January 2001
In response to phenobarbital (PB) and other PB-type inducers, the
nuclear receptor CAR translocates to the mouse liver nucleus (T. Kawamoto et al., Mol. Cell. Biol. 19:6318-6322, 1999). To define the
translocation mechanism, fluorescent protein-tagged human CAR (hCAR)
was expressed in the mouse livers using the in situ DNA injection and
gene delivery systems. As in the wild-type hCAR, the truncated receptor
lacking the C-terminal 10 residues (i.e., AF2 domain) translocated to
the nucleus, indicating that the PB-inducible translocation is AF2
independent. Deletion of the 30 C-terminal residues abolished the
receptor translocation, and subsequent site-directed mutagenesis
delineated the PB-inducible translocation activity of the receptor to
the peptide L313GLL316AEL319. Ala
mutations of Leu313, Leu316, or Leu319 abrogated the translocation of
CAR in the livers, while those of Leu312 or Leu315 did not affect the
nuclear translocation. The leucine-rich peptide dictates the nuclear
translocation of hCAR in response to various PB-type inducers and
appears to be conserved in the mouse and rat receptors.
*
Corresponding author. Mailing address: Pharmacogenetics
Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709. Phone: (919)
541-2404. Fax: (919) 541-0696. E-mail:
negishi{at}niehs.nih.gov.
Molecular and Cellular Biology, April 2001, p. 2838-2846, Vol. 21, No. 8
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.8.2838-2846.2001
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