INVESTIGADORES
HALPERIN Julia
congresos y reuniones científicas
Título:
Prolactin Signaling Through the Short Form of Its Receptor Represses Foxo3 and Map Kinase Pathways and Activates NFAT Transcription Factor
Autor/es:
Y. SANGEETA DEVI, AURORA SHEHU, JULIA HALPERIN, JIFANG MAO, JAMIE LE AND GEULA GIBORI
Lugar:
San Francisco, USA
Reunión:
Congreso; The Endocrine Society's 90th Annual Meeting; 2008
Institución organizadora:
The Endocrine Society
Resumen:
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PRL is critical for the normal
function of the ovary in rodents that express both the short (PRL-RS) and long
(PRL-RL) form of its cognate receptors. We have recently shown that PRL
signaling through PRL-RS in mice expressing only this receptor causes abnormal
follicular development and premature ovarian failure suggesting a distinct role
of PRL-RS in follicular development and survival.
In this investigation we examinedIn the present investigationIn this
investigation the mechanism by which PRL signaling through
PRL-RS causes massive follicular death. To this end, we found that
Foxo3, a transcription factor known to regulate follicular development, is
profoundly down regulated by PRL signaling through PRL-RS.
Using a cell line expressing only PRL-RS, we show that PRL induces Foxo3
protein degradation through a proteasomal-dependent pathway; independent of
Jak2 and AKT activation. The degradation of Foxo3 protein in the ovary is
accompanied by PRL/PRL-RS mediated activation of calcineurin (a phosphatase
that stimulates NFAT transcription factor) as well as inhibition of GSK3 (a kinase which
inactivates NFAT). We also
found that PRL, signaling through PRL-RS, induces nuclear translocation and
stimulates DNA binding activity of NFAT transcription factor. PRL mediated
activation of NFAT is not seen in cells expressing PRL-RL indicating that
activation of the calcineurin/GSK3/NFAT pathway by PRL is solely through
PRL-RS. Of great interest is our finding that the activity of p38 MAP kinase, known to be stimulated under
inflammatory cytokines and osmotic shock as a cell survival response, is
totally repressed by PRL signaling through PRL-RS. ATF-2 and ELK-1, the
downstream targets of p38 MAP kinase, are also severely inhibited by PRL
signaling through PRL-RS. However, the upstream kinases MKK3/6 (that phosphorylates
and activates p38 MAPK) and MLK3 are not affected by PRL suggesting involvement
of phosphatases in the inhibition of p38 MAPK. Surprisingly, there is no change
in the expression levels of immediate early genes Map Kinase Phosphatase (MKP)1
and MKP5, known to deactivate p38 MAPK.
However, we observed a marked increase in SHP2 phosphatase activity in
response to PRL in cells co-transfected with PRL-RS and JAK2. Taken together,
the results of this investigation reveal novel PRL/PRL-RS signaling pathways,
which may play important roles in follicular development and survival.
Supported by NIH HD12356, HD11119, U54HD40093, HL007692, The American
Physiological Society.
