Down-regulation of E-cadherin expression is a hallmark of a key developmental program termed the epithelial-mesenchymal transition (EMT), a process often exploited by cancer cells that display an invasive phenotype. The zinc finger transcription factor, Snail, is a powerful represser of E-cadherin gene expression that can function alone or together with the Wnt signaling cascade to induce EMT in normal as well neoplastic cells. In recent studies, we demonstrated that the Snail protein is embedded with beta-catenin-like motifs supporting its phosphorylation by GSK3beta and its subsequent beta-TrCP-directed ubiquitination and proteasomal degradation. Further, an operational model has been established wherein canonical Wnt signaling stabilizes intracellular levels of Snail and beta-catenin in cooperative fashion to engage transcriptional mechanisms that control the EMT program. Based on a body of new preliminary data, we now identify a novel regulatory cascade wherein canonical Wnt signaling and the beta- catenin/TCF transcriptional cascade initiate EMT by inducing the Axin2-dependent regulation of GSK3beta nucleo-cytoplasmic trafficking. By triggering nuclear GSK3beta export, nuclear Snail protein half-life is stabilized and a classic EMT program engaged - including cancer cell invasion and intravasation - via a process linked to the expression of membrane-anchored metalloproteinase gene family members. As such, we now propose to i) characterize the Wnt-initiated regulation of carcinoma cell EMT by the Snail/beta-catenin/TCF axis, ii) define the Snail-dependent regulation of beta-catenin/TCF-induced EMT by Axin2, iii) define the structure-function relationships underlying Axin2 nucleo-cytoplasmic trafficking and Snail-dependent EMT and iv) characterize the Axin2-dependent control of GSK3beta nucleo-cytoplasmic trafficking and its impact on Snail-dependent EMT. These studies should not only define the interlocking role of Wnt, beta-catenin/TCF and Snail in regulating EMT in cancer, but also identify new targets for therapeutic intervention. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA116516-02
Application #
7288716
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
2006-09-20
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$235,778
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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