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J. Biol. Chem., Vol. 278, Issue 13, 11471-11479, March 28, 2003
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From the Department of Gene Regulation, Bone and Inflammation
Research, Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, Indiana 46285
Nuclear receptors mediate gene activation through
ligand-dependent interaction with coactivators. We
previously cloned and characterized thyroid hormone
receptor-binding protein, TRBP (NcoA6: AIB3/ASC-2/RAP250/PRIP/TRBP/NRC), as an
LXXLL-containing coactivator that associates with
coactivator complexes through its C terminus. To search for protein
factors involved in TRBP action, we identified a distinct set of
proteins from HeLa nuclear extract that interacts with the C terminus
of TRBP. Analysis by mass spectrometric protein sequencing revealed a
DNA-dependent protein kinase (DNA-PK) complex including its
catalytic subunit and regulatory subunits, Ku70 and Ku86. DNA-PK is a
heterotrimeric nuclear phosphatidylinositol 3-kinase that functions in
DNA repair, recombination, and transcriptional regulation. DNA-PK
phosphorylates TRBP at its C-terminal region, which directly interacts
with Ku70 but not Ku86 in vitro. In addition, in the
absence of DNA, TRBP itself activates DNA-PK, and the TRBP-stimulated DNA-PK activity has an altered phosphorylation pattern from
DNA-stimulated activity. An anti-TRBP antibody inhibits TRBP-induced
kinase activity, suggesting that protein content of TRBP is responsible
for the stimulation of DNA-independent kinase activity. Furthermore, in DNA-PK-deficient scid cells, TRBP-mediated transactivation
is significantly impaired, and nuclear localization of TRBP is altered. The activation of DNA-PK in the absence of DNA ends by the coactivator TRBP suggests a novel mechanism of coactivator-stimulated DNA-PK phosphorylation in transcriptional regulation.
Nuclear Receptor Coactivator Thyroid Hormone Receptor-binding
Protein (TRBP) Interacts with and Stimulates Its Associated
DNA-dependent Protein Kinase*
and
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Eli Lilly and Co.,
Lilly Corporate Center, Bldg. 98/C, Drop Code 0434, Indianapolis, IN
46285. Tel.: 317-433-5237; Fax: 317-276-1414; E-mail:
kol@lilly.com.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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