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J. Biol. Chem., Vol. 275, Issue 48, 37429-37435, December 1, 2000
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From the Medizinische Klinik IV, Universität
Erlangen-Nürnberg, Loschgestrasse 8, D-91054 Erlangen,
Germany
Expression of connective tissue growth factor
(CTGF) was induced in renal mesangial cells by activation of
heptahelical receptors by serotonin (5-HT) and lysophosphatidic acid
(LPA). Induction of CTGF mRNA was transient with
maximal expression after 1 to 2 h, whereas induction of
CTGF by transforming growth factor beta (TGF-
Induction of Connective Tissue Growth Factor by Activation of
Heptahelical Receptors
MODULATION BY Rho PROTEINS AND THE ACTIN CYTOSKELETON*
,,
) increased
over time. In contrast to the induction of other early response genes
(Egr-1 and cyclooxygenase-2), LPA-mediated induction of CTGF was pertussis toxin-insensitive and
independent of p42/44 MAP kinase activation. 5-HT-mediated
CTGF induction was due to activation of 5-HT2A
receptors and likewise independent of p42/44 MAP kinase activation.
Upon stimulation, enhanced levels of CTGF protein were detected in
cellular homogenates, whereas no protein was detectable in cell culture
supernatants. Inhibition of proteins of the Rho family by toxin B
abrogated basal as well as CTGF expression stimulated by
LPA, 5-HT, and TGF-. Inhibition of the downstream mediator of
RhoA, the Rho kinase by Y-27632 partially reduced induction of
CTGF by LPA and TGF-. Toxin B not only affected gene
expression, but disrupted the actin cytoskeleton similarly as observed
after treatment with cytochalasin D. Disassembly of actin stress fibers
by cytochalasin D partially reduced basal and stimulated
CTGF expression. These data indicate that an intact actin
cytoskeleton is critical for the expression of CTGF.
Elimination of the input of Rho proteins by toxin B, however, was
significantly more effective and their effect on CTGF
expression thus goes beyond disruption of the cytoskeleton. These
findings thus establish activation of heptahelical receptors coupled to
pertussis toxin-insensitive G proteins as a novel signaling pathway to
induce CTGF. Proteins of the Rho family and an intact
cytoskeleton were identified as critical determinants of
CTGF expression induced by LPA and 5-HT, and also by
TGF-.
*
This work was supported by the Deutsche
Forschungsgemeinschaft, Go 413-8 and SFB 423, B3.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.
Both authors contributed equally to this manuscript.
§
To whom correspondence should be addressed: Tel.:
49-9131-853-9201; Fax: 49-9131-853-9202; E-mail:
Goppelt-Struebe@rzmail.uni-erlangen.de.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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