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Transforming growth factor-β1 induces apoptosis through Fas ligand-independent activation of the Fas death pathway in human gastric SNU-620 carcinoma cells

Cited 73 time in Web of Science Cited 78 time in Scopus
Authors
Kim, Sang Gyun; Jong, Hyun-Soon; Kim, Tae-You; Lee, Jung Weon; Kim, Noe Kyeong; Hong, Seung Hwan; Bang, Yung-Jue
Issue Date
2004-02
Citation
Molecular Biology of the Cell, Vol.15 No.2, pp.420-434
Abstract
To date, two major apoptotic pathways, the death receptor and the mitochondrial pathway, have been well documented in mammalian cells. However, the involvement of these two apoptotic pathways, particularly the death receptor pathway, in transforming growth factor-beta1 (TGF-beta1)-induced apoptosis is not well understood. Herein, we report that apoptosis of human gastric SNU-620 carcinoma cells induced by TGF-beta1 is caused by the Fas death pathway in a Fas ligand-independent manner, and that the Fas death pathway activated by TGF-beta1 is linked to the mitochondrial apoptotic pathway via Bid mediation. We showed that TGF-beta1 induced the expression and activation of Fas and the subsequent caspase-8-mediated Bid cleavage. Interestingly, expression of dominant negative FADD and treatment with caspase-8 inhibitor efficiently prevented TGF-beta1-induced apoptosis, whereas the treatment with an activating CH11 or a neutralizing ZB4 anti-Fas antibody, recombinant Fas ligand, or Fas-Fc chimera did not affect activation of Fas and the subsequent induction of apoptosis by TGF-beta1. We further demonstrated that TGF-beta1 also activates the mitochondrial pathway showing Bid-mediated loss of mitochondrial membrane potential and subsequent cytochrome c release associated with the activations of caspase-9 and the effector caspases. Moreover, all these apoptotic events induced by TGF-beta1 were found to be effectively inhibited by Smad3 knockdown and also completely abrogated by Smad7 expression, suggesting the involvement of the Smad3 pathway upstream of the Fas death pathway by TGF-beta1.
ISSN
1059-1524
URI
https://hdl.handle.net/10371/173185
DOI
https://doi.org/10.1091/mbc.E03-04-0201
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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