Protection against anoikis and down-regulation of cadherin expression by a regulatable beta-catenin protein.
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.
Weng
Zhigang
Z
Cambridge Genomics Center, Aventis Pharmaceuticals, Cambridge, Massachusetts 02139, USA. gweng@ipi.com
Xin
Mei
M
Pablo
Lourdes
L
Grueneberg
Dorre
D
Hagel
Margit
M
Bain
Gerard
G
Müller
Thomas
T
Papkoff
Jackie
J
D000818:Animals; D023102:Anoikis; D015820:Cadherins / Q000378:metabolism*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000502:physiology; D004285:Dogs; D015536:Down-Regulation / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D017930:Genes, Reporter; D020935:MAP Kinase Signaling System; D016297:Mutagenesis, Site-Directed; D015534:Trans-Activators; D051176:beta Catenin
D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin