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J. Biol. Chem., Vol. 277, Issue 24, 21285-21290, June 14, 2002
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From the The insulin-like growth factor-binding protein 4 (IGFBP-4), the most abundant IGF-binding protein produced by rodent
smooth muscle cells (SMC), is degraded by specific protease(s)
potentially releasing IGF-I for local bioactivity. IGFBP-4 protease(s)
recognizes basic residues within the midregion of the molecule.
We constructed a mutant IGFBP-4 with the cleavage domain substitution
119-KHMAKVRDRSKMK-133 to
119-AAMAAVADASAMA-133.
Myc-tagged native and IGFBP-4.7A retained equivalent IGF-I binding
affinity. Whereas native IGFBP-4 was cleaved by SMC-conditioned medium,
IGFBP-4.7A was completely resistant to proteolysis. To explore the
function of the protease-resistant IGFBP-4 in vivo,
expression of the mutant and native proteins was targeted to SMC of
transgenic mice by means of a smooth muscle
Targeted Expression of a Protease-resistant IGFBP-4 Mutant in
Smooth Muscle of Transgenic Mice Results in IGFBP-4 Stabilization and
Smooth Muscle Hypotrophy*
,,,¶
Divisions of Endocrinology and Metabolism,
University of Cincinnati College of Medicine and the
§ Children's Hospital Medical Center, Cincinnati, Ohio
45267-0547
-actin promoter.
Transgene expression was confined to SMC-rich tissues in all lines.
Bladder and aortic immunoreactive IGFBP-4/transgene mRNA ratios in
SMP8-BP4.7A mice were increased by 2- to 4-fold relative to SMP8-BP4
mice, indicating that the IGFBP-4.7A protein was stabilized in
vivo. SMP8-BP4.7A mice had lower aortic, bladder, and stomach
weight and intestinal length relative to SMP8-BP4 counterparts matched
for protein expression by Western blotting. Thus, IGFBP-4.7A
results in greater growth inhibition than equivalent levels of native
IGFBP-4 in vivo, demonstrating a role for IGFBP-4 proteolysis in the regulation of IGF-I action.
*
This work was supported by Public Health Service Grant
DK54216.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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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