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Mise, N. ; Savai, R.* ; Yu, H. ; Schwarz, J. ; Kaminski, N.* ; Eickelberg, O.

Zyxin is a Transforming Growth Factor-β (TGF-β)/Smad3 target gene that regulates lung cancer cell motility via integrin α5β1.

J. Biol. Chem. 287, 31393-31405 (2012)
DOI PMC
Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
Although TGF-beta acts as a tumor suppressor in normal tissues and in early carcinogenesis, these tumor suppressor effects are lost in advanced malignancies. Single cell migration and epithelial-mesenchymal transition (EMT), both of which are regulated by TGF-beta, are critical steps in mediating cancer progression. Here, we sought to identify novel direct targets of TGF-beta signaling in lung cancer cells and have indentified the zyxin gene as a target of Smad3-mediated TGF-beta 1 signaling. Zyxin concentrates at focal adhesions and along the actin cytoskeleton; as such, we hypothesized that cytoskeletal organization, motility, and EMT in response to TGF-beta 1 might be regulated by zyxin expression. We show that TGF-beta 1 treatment of lung cancer cells caused rapid phospho-Smad3-dependent expression of zyxin. Zyxin expression was critical for the formation and integrity of cell adherens junctions. Silencing of zyxin decreased expression of the focal adhesion protein vasodilator-activated phosphoprotein (VASP), although the formation and morphology of focal adhesions remained unchanged. Zyxin-depleted cells displayed significantly increased integrin alpha 5 beta 1 levels, accompanied by enhanced adhesion to fibronectin and acquisition of a mesenchymal phenotype in response to TGF-beta 1. Zyxin silencing led to elevated integrin alpha 5 beta 1-dependent single cell motility. Importantly, these features are mirrored in the K-ras-driven mouse model of lung cancer. Here, lung tumors revealed decreased levels of both zyxin and phospho-Smad3 when compared with normal tissues. Our data thus demonstrate that zyxin is a novel functional target and effector of TGF-beta signaling in lung cancer. By regulating cell-cell junctions, integrin alpha 5 beta 1 expression, and cell-extracellular matrix adhesion, zyxin may regulate cancer cell motility and EMT during lung cancer development and progression.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter EPITHELIAL-MESENCHYMAL TRANSITIONS; TGF-BETA; ACTIN-POLYMERIZATION; TUMOR-SUPPRESSOR; ALPHA-ACTININ; II RECEPTOR; PROTEIN; ADHESION; TRANSDIFFERENTIATION; SMAD3
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Zeitschrift Journal of Biological Chemistry, The
Quellenangaben Band: 287, Heft: 37, Seiten: 31393-31405 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)