INVESTIGADORES
HALPERIN Julia
congresos y reuniones científicas
Título:
Prolactin signaling through the short isoform of its receptor activates the inflammatory pathway
Autor/es:
SANGEETA DEVI, AURORA SHEHU, JULIA HALPERIN, CARLOS STOCCO, NADINE BINART AND GEULA GIBORI
Lugar:
Evanston, USA
Reunión:
Simposio; 14. 27th Annual Minisymposium on Reproductive Biology; 2006
Institución organizadora:
Northwestern University
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
