Transforming growth factor β enhances epithelial cell survival via Akt-dependent regulation of FKHRL1

被引:151
作者
Shin, I
Bakin, AV
Rodeck, U
Brunet, A
Arteaga, CL [1 ]
机构
[1] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA
[4] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
[5] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA
[6] Harvard Univ, Sch Med, Childrens Hosp, Div Neurosci, Boston, MA 02115 USA
关键词
D O I
10.1091/mbc.12.11.3328
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The Forkhead family of transcription factors participates in the induction of death-related genes. In NMuMG and 4T1 mammary epithelial cells, transforming growth factor beta (TGF beta) induced phosphorylation and cytoplasmic retention of the Forkhead factor FKHRL1, while reducing FHKRL1-dependent transcriptional activity. TGF beta -induced FKHRL1 phosphorylation and nuclear exclusion were inhibited by LY294002, an inhibitor of phosphatidylinositol-3 kinase. A triple mutant of FKHRL1, in which all three Akt phosphorylation sites have been mutated (TMFKHRL1), did not translocate to the cytoplasm in response to TGF beta. In HaCaT keratinocytes, expression of dominant-negative Akt prevented TGF beta -induced 1) reduction of Forkhead-dependent transcription, 2) FKHRL1 phosphorylation, and 3) nuclear exclusion of FKRHL1. Forced expression of either wild-type (WT) or TM-FKHRL1, but not a FKHRL1 mutant with deletion of the transactivation domain, resulted in NMuMG mammary cell apoptosis., Evidence of nuclear fragmentation colocalized to cells with expression of WT- or TM-FKHRL1. The apoptotic effect of WT-FKHRL1 but not TM-FKHRL1 was prevented by exogenous TGF beta. Serum starvation-induced apoptosis was also inhibited by TGF beta in NMuMG and HaCaT cells. Finally, dominant-negative Akt abrogated the antiapoptotic effect of TGF beta. Taken together, these data suggest that TGF beta may play a role in epithelial cell survival via Akt-dependent regulation of FKHRL1.
引用
收藏
页码:3328 / 3339
页数:12
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