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

I. Shin, A. V. Bakin, U. Rodeck, A. Brunet, C. L. Arteaga

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

The Forkhead family of transcription factors participates in the induction of death-related genes. In NMuMG and 4T1 mammary epithelial cells, transforming growth factor β (TGFβ) induced phosphorylation and cytoplasmic retention of the Forkhead factor FKHRL1, while reducing FHKRL1-dependent transcriptional activity. TGFβ-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 (TM-FKHRL1), did not translocate to the cytoplasm in response to TGFβ. In HaCaT keratinocytes, expression of dominant-negative Akt prevented TGFβ-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 TGFβ. Serum starvation-induced apoptosis was also inhibited by TGFβ in NMuMG and HaCaT cells. Finally, dominant-negative Akt abrogated the antiapoptotic effect of TGFβ. Taken together, these data suggest that TGFβ may play a role in epithelial cell survival via Akt-dependent regulation of FKHRL1.

Original languageEnglish (US)
Pages (from-to)3328-3339
Number of pages12
JournalMolecular biology of the cell
Volume12
Issue number11
DOIs
StatePublished - Jan 1 2001

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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