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J. Biol. Chem., Vol. 278, Issue 9, 7718-7724, February 28, 2003
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From the Transforming growth factor-
Transforming Growth Factor-
1 Mutations in Camurati-Engelmann
Disease Lead to Increased Signaling by Altering either Activation or
Secretion of the Mutant Protein*
§,
,
Department of Medical Genetics,
University of Antwerp, 2610 Antwerp, Belgium, ¶ Division of
Cellular Biochemistry, The Netherlands Cancer Institute, 1066 CX
Amsterdam, The Netherlands, ** Department of Medicine and
Therapeutics, University of Aberdeen Medical School, Aberdeen AB252ZD,
United Kingdom, and §§ Institute of Human Genetics, Aachen
University, 52074 Aachen, Germany
1
(TGF-1) is secreted as a latent precursor, consisting of a homodimer
of the latency-associated peptide and the mature peptide. TGF-1 can
only exert its many functions after going from this latent to an active
state, in which the binding site of the mature peptide for its receptor is no longer shielded by the latency-associated peptide. We and others
reported that mutations in TGFB1 cause Camurati-Engelmann disease, a rare bone disorder. Until now, seven mutations have been
published. In this study, we investigate the effect of the LLL12-13ins, Y81H, R218C, H222D, and C225R mutations on the
functioning of TGF-1 in vitro. A luciferase reporter
assay specific for TGF--induced transcriptional response with wild
type and mutant TGF-1 constructs showed a positive effect of all
mutations on TGF-1 activity. By way of enzyme-linked immunosorbent
assay, we found that in the R218C, H222D, and C225R mutant
constructs, this effect is caused by an increase in active TGF-1 in
the medium of transfected cells. The LLL12-13ins and Y81H mutations on
the contrary have a profound effect on secretion; a decreased amount of
TGF-1 is secreted, but the increased luciferase activity shows that
the intracellular accumulation of (aberrant) TGF-1 can initiate an enhanced transcriptional response, suggesting the existence of an
alternative signaling pathway. Our data indicate that the mutations in
the signal peptide and latency-associated peptide facilitate TGF-1
signaling, thus causing Camurati-Engelmann disease.
*
This work was supported in part by Grant G.0404.00 from the
"Fonds voor Wetenschappelijk onderzoek" and by an Interuniversity Attraction Pole grant (to W. V. H.).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 the Netherlands Institute for Earth and Life
Sciences (ALW 809.67.024).
To whom correspondence should be addressed: Dept. of Medical
Genetics, University of Antwerp (T6), Universiteitsplein 1, 2610 Antwerp, Belgium. Tel.: 32-3-820-25-85; Fax: 32-3-820-25-66; E-mail: vhul@uia.ua.ac.be.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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