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J. Biol. Chem., Vol. 276, Issue 49, 46661-46670, December 7, 2001
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From the Institut für Zellbiologie, Abteilung
Molekularbiologie, Universität Tübingen, Auf der
Morgenstelle 15, 72076 Tübingen, Germany
The majority of breast cancers metastasizing to
bone secrete parathyroid hormone-related protein (PTHrP). PTHrP induces
local osteolysis that leads to activation of bone matrix-borne
transforming growth factor
Transforming Growth Factor
Regulates Parathyroid
Hormone-related Protein Expression in MDA-MB-231 Breast Cancer Cells
through a Novel Smad/Ets Synergism*
,
(TGF). In turn, TGF stimulates
PTHrP expression and, thereby, accelerates bone destruction. We studied
the mechanism by which TGF activates PTHrP in invasive MDA-MB-231
breast cancer cells. We demonstrate that TGF1 up-regulates
specifically the level of PTHrP P3 promoter-derived RNA in an
actinomycin D-sensitive fashion. Transient transfection studies
revealed that TGF1 and its effector Smad3 are able to activate the
P3 promoter. This effect depended upon an AGAC box and a previously
described Ets binding site. Addition of Ets1 greatly enhanced the
Smad3/TGF-mediated activation. Ets2 had also some effect, whereas
other Ets proteins, Elf-1, Ese-1, and Erf-1, failed to cooperate with
Smad3. In comparison, Ets1 did not increase Smad3/TGF-induced
stimulation of the TGF-responsive plasminogen activator inhibitor 1 (PAI-1) promoter. Smad3 and Smad4 were able to specifically interact
with the PTHrP P3-AGAC box and to bind to the P3 promoter together with
Ets1. Inhibition of endogenous Ets1 expression by calphostin C
abrogated TGF-induced up-regulation of the P3 transcript, whereas it
did not affect the TGF effect on PAI expression. In TGF receptor
II- and Ets1-deficient, noninvasive MCF-7 breast cancer cells, TGF1
neither influenced endogenous PTHrP expression nor stimulated the PTHrP
P3 promoter. These data suggest that TGF activates PTHrP expression
by specifically up-regulating transcription from the PTHrP P3
promoter through a novel Smad3/Ets1 synergism.
*
This work was supported by Grant 10-1601-No3 from the Dr.
Mildred Scheel Stiftung.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.
Present address: Friedrich Miescher Inst., 4058 Basel, Switzerland.
§
To whom correspondence should be addressed. Tel.:
49-7071-297-8893; Fax: 49-7071-295359; E-mail:
juergen.dittmer@uni-tuebingen.de.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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