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Vol. 12, Issue 11, 3328-3339, November 2001
Enhances Epithelial Cell Survival
via Akt-dependent Regulation of FKHRL1
and
¶
Departments of *Medicine and §Cancer Biology,
Vanderbilt University School of Medicine,
The Forkhead family of transcription factors participates in the
induction of death-related genes. In NMuMG and 4T1 mammary epithelial
cells, transforming growth factor Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
37232; Department of Dermatology, Kimmel Cancer Center
and Thomas Jefferson University, Philadelphia, Pennsylvania 19107; and
Division of Neuroscience, Children's Hospital and
Department of Neurobiology, Harvard Medical School, Boston,
Massachusetts 02115
(TGF) induced phosphorylation
and cytoplasmic retention of the Forkhead factor FKHRL1, while reducing
FHKRL1-dependent transcriptional activity. TGF-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
TGF. In HaCaT keratinocytes, expression of dominant-negative Akt
prevented TGF-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. Serum starvation-induced apoptosis was also inhibited
by TGF in NMuMG and HaCaT cells. Finally, dominant-negative Akt
abrogated the antiapoptotic effect of TGF. Taken together, these
data suggest that TGF may play a role in epithelial cell survival
via Akt-dependent regulation of FKHRL1.
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