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Originally published In Press as doi:10.1074/jbc.M105331200 on March 19, 2002

J. Biol. Chem., Vol. 277, Issue 21, 18677-18686, May 24, 2002
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Protection against Anoikis and Down-regulation of Cadherin Expression by a Regulatable beta -Catenin Protein*

Zhigang WengDagger §, Mei Xin, Lourdes Pablo||, Dorre Grueneberg, Margit HagelDagger , Gerard Bain, Thomas Müller, and Jackie Papkoff**

From the Cambridge Genomics Center, Aventis Pharmaceuticals, Cambridge, Massachusetts 02139

beta -Catenin signaling plays a key role in a variety of cellular contexts during embryonic development and tissue differentiation. Aberrant beta -catenin signaling has also been implicated in promoting human colorectal carcinomas as well as a variety of other cancers. To study the molecular and cellular biological functions of beta -catenin in a controlled fashion, we created a regulatable form of activated beta -catenin by fusion to a modified estrogen receptor (ER) ligand binding domain (G525R). Transfection of tissue culture cells with expression vectors encoding this hybrid protein allows the signal transduction function of beta -catenin to be induced by the synthetic estrogen, 4-hydroxytamoxifen, leading to regulated activation of a beta -catenin-lymphocyte enhancer-binding factor-dependent reporter gene as well as induction of endogenous cyclin D1 expression. The activation of ER-beta -catenin signaling rescues RK3E cells from anoikis and correlates with an increased phosphorylation of mitogen-activated protein kinase. The inhibition of anoikis by ER-beta -catenin can be abolished by a mitogen-activated protein kinase pathway inhibitor, PD98059. Evidence is also provided to show that ER-beta -catenin down-regulates cadherin protein levels. These findings support a key role for activated beta -catenin signaling in processes that contribute to tumor formation and progression.

* 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.

Dagger Present address: Infinity Pharmaceuticals Inc., 650 Albany St., Boston, MA 02118.

§ To whom correspondence should be addressed. Tel.: 617-896-2938; Fax: 617-859-9703; E-mail: gweng@ipi.com.

Present address: Biogen, Inc., 14 Cambridge Center, Cambridge, MA 02142.

|| Present address: Virginia Commonwealth University, Richmond, VA 23284.

** Present address: diaDexus, Inc., 343 Oyster Point Blvd., South San Francisco CA 94080.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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