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Beta-3 integrins enhance TGF-beta-me...

University of Colorado Health Sciences Center.

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Beta-3 integrins enhance TGF-beta-mediated tumor progression in mammary epithelial cells.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Beta-3 integrins enhance TGF-beta-mediated tumor progression in mammary epithelial cells./
作者:	Galliher, Amy Jo.
面頁冊數:	128 p.
附註:	Adviser: William P. Schiemann.
Contained By:	Dissertation Abstracts International68-08B.
標題:	Biology, Cell. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3277178
ISBN:	9780549190356

Beta-3 integrins enhance TGF-beta-mediated tumor progression in mammary epithelial cells.
Galliher, Amy Jo.

Beta-3 integrins enhance TGF-beta-mediated tumor progression in mammary epithelial cells. - 128 p.

Adviser: William P. Schiemann.

Thesis (Ph.D.)--University of Colorado Health Sciences Center, 2007.

Genetic and epigenetic events often negate the cytostatic function of transforming growth factor-beta (TGF-beta) in mammary epithelial cells (MECs), ultimately enabling malignant MECs to proliferate, invade, and metastasize when stimulated by TGF-beta. The molecular mechanisms underlying this phenotypic conversion of TGF-beta function during mammary tumorigenesis remain poorly defined. We established alphavbeta3 integrin and Src as essential mediators of TGF-beta-stimulated p38 MAP kinase activation, invasion, and epithelial-to-mesenchymal transition (EMT) in normal and malignant MECs. Mechanistically, TGF-beta stimulation induced alphavbeta3 integrin expression in MECs, an event which coincided with the initiation of EMT. beta3 integrin interacted physically with the TGF-beta type II receptor (TbetaR-II), leading to its Tyr phosphorylation on Y284 by Src kinase. Interestingly, Y284 of T(3R-II was required for TGF-R-mediated p38 MAPK activation and invasion in murine 4T1 breast cancer cells. Accordingly, Src-mediated phosphorylation of Y284 coordinated the docking of the SH2 domains of Grb2 and Shc to TbetaR-II, thereby associating these adapter proteins to MAP kinase activation by TGF-beta. Introducing siRNAs against Grb2 significantly impaired the ability of TGF-beta to stimulate p38 MAPK, undergo EMT, and invade synthetic basement membranes. Finally, we observed that expression of Src-resistant TbetaR-II mutants (i.e., Y284F-TbetaR-II) in 4T1 breast cancer cells inhibited their growth in mice, as well as their metastasis to the lungs. Collectively, our findings have identified a novel alphavbeta3 integrin:Src:Y284-TbetaR-II signaling axis that promotes oncogenic signaling by TGF-beta in malignant MECs, and suggest that antagonizing this signaling axis may one day prove beneficial in treating patients with metastatic breast cancers. The form and content of this abstract are approved. I recommend its publication.

ISBN: 9780549190356Subjects--Topical Terms:

1017686
Biology, Cell.

Beta-3 integrins enhance TGF-beta-mediated tumor progression in mammary epithelial cells.
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502 $a Thesis (Ph.D.)--University of Colorado Health Sciences Center, 2007.
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