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J. Biol. Chem., Vol. 275, Issue 31, 23891-23898, August 4, 2000
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From the Department of Biology, Indiana University-Purdue
University, Indianapolis, Indiana 46202-5132, the
LIM homeodomain transcription factors regulate
development in complex organisms. To characterize the molecular signals
required for the nuclear localization of these proteins, we examined
the Lhx3 factor. Lhx3 is essential for pituitary organogenesis and motor neuron specification. By using functional fluorescent
derivatives, we demonstrate that Lhx3 is found in both the nucleoplasm
and nuclear matrix. Three nuclear localization signals were mapped within the homeodomain, and one was located in the carboxyl terminus. The homeodomain also serves as the nuclear matrix targeting sequence. No individual signal is alone required for nuclear localization of
Lhx3; the signals work in combinatorial fashion. Specific combinations of these signals transferred nuclear localization to cytoplasmic proteins. Mutation of nuclear localization signals within the homeodomain inhibited Lhx3 transcriptional function. By contrast, mutation of the carboxyl-terminal signal activated Lhx3, indicating that this region is critical to transcriptional activity and may be a
target of regulatory pathways. The pattern of conservation of the
nuclear localization and nuclear matrix targeting signals suggests that
the LIM homeodomain factors use similar mechanisms for subcellular
localization. Furthermore, upon nuclear entry, association of Lhx3 with
the nuclear matrix may contribute to LIM homeodomain factor
interaction with other classes of transcription factors.
The Homeodomain Coordinates Nuclear Entry of the Lhx3
Neuroendocrine Transcription Factor and Association with the
Nuclear Matrix*
,
Department of Medicine, Division of Nephrology,
Renal Epithelial Biology Experimental Laboratory Imaging
Facility, Indiana University School of Medicine,
Indianapolis, Indiana 46202-5113, the § Department of
Anatomy and Cell Biology, Indiana University School of Medicine, and
the ¶ Department of Periodontics, Indiana University School of
Dentistry, Indianapolis, Indiana 46202
*
This work was supported by a grant from the National Science
Foundation (to S. J. R.), a grant from the NRICGP/United States Department of Agriculture (to S. J. R.), and Grant NIDR DE0126 53-01 from the National Institutes of Health (to J. P. B.).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: Dept. of Biology,
Indiana University-Purdue University Indianapolis, 723 West Michigan
St., Indianapolis, IN 46202-5132. Tel.: 317-278-1797; Fax:
317-274-2846; E-mail: srhodes@iupui.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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