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Maetzel, D. ; Denzel, S. ; Mack, B.* ; Canis, M.* ; Went, P.* ; Benk, M. ; Kieu, C.* ; Papior, P. ; Baeuerle, P.A.* ; Münz, M. ; Gires, O.

Nuclear signalling by tumour-associated antigen EpCAM.

Nat. Cell Biol. 11, 162-171 (2009)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
EpCAM was found to be overexpressed on epithelial progenitors, carcinomas and cancer-initiating cells. The role of EpCAM in proliferation, and its association with cancer is poorly explained by proposed cell adhesion functions. Here we show that regulated intramembrane proteolysis activates EpCAM as a mitogenic signal transducer in vitro and in vivo. This involves shedding of its ectodomain EpEX and nuclear translocation of its intracellular domain EpICD. Cleavage of EpCAM is sequentially catalysed by TACE and presenilin-2. Pharmacological inhibition or genetic silencing of either protease impairs growth-promoting signalling by EpCAM, which is compensated for by EpICD. Released EpICD associates with FHL2, beta-catenin and Lef-1 to form a nuclear complex that contacts DNA at Lef-1 consensus sites, induces gene transcription and is oncogenic in immunodeficient mice. In patients, EpICD was found in nuclei of colon carcinoma but not of normal tissue. Nuclear signalling of EpCAM explains how EpCAM functions in cell proliferation.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter dependent gamma-secretase; ep-cam; breast-cancer; beta-catenin; cell-proliferation; adhesion molecule; colorectal-cancer; stem-cells; c-myc; target
Sprache
Veröffentlichungsjahr 2009
HGF-Berichtsjahr 2009
ISSN (print) / ISBN 1465-7392
e-ISSN 1476-4679
Zeitschrift Nature Cell Biology
Quellenangaben Band: 11, Heft: 2, Seiten: 162-171 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Begutachtungsstatus Peer reviewed
Institut(e) CCG Molecular Oncology (AGV-KON)
Research Unit Gene Vector (AGV)
POF Topic(s)
30203 - Molecular Targets and Therapies
Forschungsfeld(er)
Immune Response and Infection
PSP-Element(e) G-520700-001
G-501500-001
DOI 10.1038/ncb1824
Scopus ID 59749103834
PubMed ID 19136966
Erfassungsdatum 2009-07-09
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