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J. Biol. Chem., Vol. 277, Issue 26, 23888-23897, June 28, 2002
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From the Winters Center For Heart Failure Research,
Molecular Cardiology Unit, Cardiology Section of Department of
Medicine, Baylor College of Medicine, Veterans Affairs Medical Center,
Houston, Texas 77030
Myotrophin/V-1 is a cytosolic
protein found at elevated levels in failing human hearts and in
postnatal cerebellum. We have previously shown that it disrupts nuclear
factor of
Myotrophin/V-1, a Protein Up-regulated in the Failing Human Heart
and in Postnatal Cerebellum, Converts NF
B p50-p65 Heterodimers to
p50-p50 and p65-p65 Homodimers*
,
B (NFB)-DNA complexes in vitro. In this
study, we demonstrated that in HeLa cells native myotrophin/V-1 is
predominantly present in the cytoplasm and translocates to the nucleus
during sustained NFB activation. Three-dimensional alignment studies
indicate that myotrophin/V-1 resembles a truncated IB
without the
signal response domain (SRD) and PEST domains. Co-immunoprecipitation
studies reveal that myotrophin/V-1 interacts with NFB proteins
in vitro; however, it remains physically associated only
with p65 and c-Rel proteins in vivo during NFB
activation. In vitro studies indicate that myotrophin/V-1
can promote the formation of p50-p50 homodimers from monomeric p50
proteins and can convert the preformed p50-p65 heterodimers into
p50-p50 and p65-p65 homodimers. Furthermore, adenovirus-mediated
overexpression of myotrophin/V-1 resulted in elevated levels of both
p50-p50 and p65-p65 homodimers exceeding the levels of p50-p65
heterodimers compared with Ad
gal-infected cells, where the levels of
p50-p65 heterodimers exceeded the levels of p50-p50 and p65-p65
homodimers. Thus, overexpression of myotrophin/V-1 during NFB
activation resulted in a qualitative shift by quantitatively reducing
the level of transactivating heterodimers while elevating the levels of
repressive p50-p50 homodimers. Correspondingly, overexpression of
myotrophin/V-1 resulted in significantly reduced B-luciferase
reporter activity. Because myotrophin/V-1 is found at elevated levels
during NFB activation in postnatal cerebellum and in failing human
hearts, this study cumulatively suggests that myotrophin/V-1 is
a regulatory protein for modulating the levels of activated NFB
dimers during this period.
*
This work was supported in part by Grant-in-aid 0050786Y (to
N. S.) from the American Heart Association, Texas affiliate.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.
Supported by Deutsche Forschungsgemeinschaft Grant KN521/1-1.
Present address: Dept. of Anesthesiology and Intensive Care Medicine,
University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
§
Present address: Dept. of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, TX 75235.
¶
Present address: Cardiovascular Research Inst., Dept. of
Medicine, University of Medicine and Dentistry at New Jersey, Newark, NJ 07103.
To whom correspondence should be addressed: Winters Center for
Heart Failure Research, 6565 Fannin St., MS524, Houston, TX 77030. Tel.: 713-441-1243; Fax: 713-441-1252;E-mail:
nats@bcm.tmc.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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