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

145 Citations (Scopus)

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
StatePublished - Dec 13 2001

Fingerprint

Transforming Growth Factors
Cell Survival
Epithelial Cells
Phosphorylation
Breast
Phosphatidylinositol 3-Kinase
Apoptosis
Forkhead Transcription Factors
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Starvation
Keratinocytes
Transcriptional Activation
Cytoplasm
Serum
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Transforming growth factor β enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. / Shin, I.; Bakin, A. V.; Rodeck, U.; Brunet, A.; Arteaga, C. L.

In: Molecular Biology of the Cell, Vol. 12, No. 11, 13.12.2001, p. 3328-3339.

Research output: Contribution to journalArticle

@article{5df2175ecc714e37a962cbfded1bfbb7,
title = "Transforming growth factor β enhances epithelial cell survival via Akt-dependent regulation of FKHRL1",
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.",
author = "I. Shin and Bakin, {A. V.} and U. Rodeck and A. Brunet and Arteaga, {C. L.}",
year = "2001",
month = "12",
day = "13",
language = "English (US)",
volume = "12",
pages = "3328--3339",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
publisher = "American Society for Cell Biology",
number = "11",

}

TY - JOUR

T1 - Transforming growth factor β enhances epithelial cell survival via Akt-dependent regulation of FKHRL1

AU - Shin, I.

AU - Bakin, A. V.

AU - Rodeck, U.

AU - Brunet, A.

AU - Arteaga, C. L.

PY - 2001/12/13

Y1 - 2001/12/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0035196587&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035196587&partnerID=8YFLogxK

M3 - Article

C2 - 11694570

AN - SCOPUS:0035196587

VL - 12

SP - 3328

EP - 3339

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

SN - 1059-1524

IS - 11

ER -