INVESTIGADORES
HALPERIN Julia
congresos y reuniones científicas
Título:
Prolactin signaling through the short isoform of its receptor activate the inflammatory pathway
Autor/es:
SANGEETA Y, SHEHU A, HALPERIN J, STOCCO CO, BINART N AND GIBORI G
Lugar:
New London, USA
Reunión:
Conferencia; Gordon Research Conference in Reproductive Tract Biology; 2006
Institución organizadora:
Gordon Research Conferences (GRC)
Resumen:
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Prolactin (PRL) has been shown to bind to two distinct receptors long
(PRL-RL) and short (PRL-RS). PRL signaling through PRL-RL activates several
pathways including STAT, PI3K and Src. However, PRL-RS mediated PRL signaling
pathways have not been elucidated to date. PRLR null mice expressing only the
PRL-RS have been generated and our analysis revealed premature follicular
activation leading to premature ovarian failure and total absence of follicles
due to massive granulosa and oocyte death. To determine how PRL signaling
through PRL-RS causes such a severe phenotype, a transcription reporter array
with consensus binding sequences for 354 transcription factors (TFs) was
performed using ovaries from PRL-RS transgene mice. PRL signaling through
PRL-RS affected profoundly DNA-binding activity of several TFs. These TFs are
involved in developmental, glucose metabolism, and immune response pathways.Interestingly, anti-inflammatory gene such as E4BP4 was downregulated while
the immune response gene, NFATc was stimulated. NFAT proteins are known to
induce proinflammatory cytokines such as TNF alpha. Indeed TNF alpha was
markedly stimulated both at the mRNA and protein levels in the PRL-RS
expressing ovary upon PRL treatment. We also observed a severe inhibition of
GSK3, a kinase which phosphorylates and inactivates NFATc, and whose deletion
leads to massive TNF alpha induced apoptosis in hepatocytes known to be rich in
PRL-RS. These results indicate that PRL signaling through PRL-RS causes
transcriptional activation of NFATc and induction of proinflammatory cytokines
such as TNF alpha leading, at least in part, to the massive cell death seen in
the ovary. In addition, we observed the MAPK pathways, important for PRL
induced cell proliferation and differentiation, were actively inhibited by PRL
signaling through PRL-RS. Taken together, these data provide, for the first
time, evidence that PRL signals through PRL-RS and causes severe upregulation
in the pathways involved in proinflammatory processes and concomitant
downregulation of those involved in proliferation and differentiation.
Furthermore, our results suggest strongly that this PRL effect plays a role in
the massive granulosa and oocyte death and the premature ovarian failure in
PRL-RS transgenic mice. Supported by NIH HD11119-28, APS fellowship