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A more recent version of this article appeared on February 1, 2003
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Submitted on March 7, 2002
Revised on October 3, 2002
Accepted on October 21, 2002
1-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TAK1 and MKK3
1 Ludwig Institute for Cancer Research, Biomedical Centre, Uppsala, Sweden
2 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
3 Division of Cellular Biochemistry, Netherlands Cancer Institute, Amsterdam, The Netherlands
* Corresponding author. E-mail address: Marene.Landstrom{at}LICR.uu.se.
The inhibitory Smad7, a direct target gene for transforming growth factor-
(TGF-), mediates TGF-1-induced apoptosis in several cell types. Here we report that apoptosis of human prostate cancer PC-3U cells induced by TGF-1 or Smad7 overexpression, is caused by a specific activation of the p38 MAP kinase pathway in a TGF--activated kinase 1 (TAK1)- and mitogen activated protein kinase kinase 3 (MKK3)-dependent manner. Expression of dominant negative p38, dominant negative MKK3, or incubation with the p38 selective inhibitor SB203580, prevented TGF-1-induced apoptosis. The expression of Smad7 was required for TGF--induced activation of MKK3 and p38 kinases, and endogenous Smad7 was found to interact with phosphorylated p38 in a ligand-dependent way. Ectopic expression of wild-type TAK1 promoted TGF-1-induced phosphorylation of p38 and apoptosis, while dominant negative TAK1 reduced TGF-1-induced phosphorylation of p38 and apoptosis. Endogenous Smad7 was found to interact with TAK1, and TAK1, MKK3 and p38 were co-immunoprecipitated with Smad7 in transiently transfected COS1 cells. Moreover, ectopically expressed Smad7 enhanced the co-immunoprecipitation of HA-MKK3 and Flag-p38, supporting the notion that Smad7 may act as a scaffolding protein and facilitate TAK1- and MKK3-mediated activation of p38.
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