Abstract: SAT 460

Apoptotic and Antiproliferative Prolactin Receptor Signaling Pathways Involved in Anterior Pituitary Homeostasis

Presenter: Jimena Ferraris


Abstract


Jimena Ferraris*1, Nataly de Dios2,Santiago Jordi Orrillo1, Martin Irizarri1, Maria Florencia Gottardo2, Adriana Seilicovich2, Vincent Goffin3 and Daniel Pisera2

1Institute of Biomedical Research, University of Buenos Aires-CONICET, Buenos Aires, Argentina, 2University of Buenos Aires-CONICET, Buenos Aires, Argentina,3Faculté de Médecine, Université Paris Descartes, Paris cedex 14, Franc

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Jimena Ferraris*1, Nataly de Dios2,Santiago Jordi Orrillo1, Martin Irizarri1, Maria Florencia Gottardo2, Adriana Seilicovich2, Vincent Goffin3 and Daniel Pisera2

1Institute of Biomedical Research, University of Buenos Aires-CONICET, Buenos Aires, Argentina, 2University of Buenos Aires-CONICET, Buenos Aires, Argentina,3Faculté de Médecine, Université Paris Descartes, Paris cedex 14, Franc

Prolactin (PRL) induces apoptosis and inhibits proliferation of lactotropes, thereby playing a key role in the regulation of anterior pituitary homeostasis (1). Our recent results suggested that activation of JAK2 and ERK1/2 kinases are involved in these atypical PRL effects (2). Since PRL-activated JAK2 can phosphorylate different STAT proteins, we here determined the participation of STAT5 and STAT3 in the apoptotic and antiproliferative effects of PRL in pituitary cells. As the PRL receptor (PRLR) activates various other signaling cascades, we also evaluated the involvement of P38 MAPK, a kinase known to regulate lactotrope homeostasis. For these studies, we used i) the GH3 somatolactotrope cell line as a model of PRL-secreting pituitary cells leading to constitutively activated PRLR signaling, ii) the pure PRLR antagonist ∆1–9-G129R-hPRL as a pan-inhibitor of PRLR signaling cascades, and iii) cascade-specific inhibitors targeting STAT5 (U51573108), STAT3 (jsi-124) or P38 (SB203580), whose efficacy and specificity were evaluated by immunofluorescence (p-STAT5 and p-STAT3) or immunoblotting (p-P38 MAPK) using phospho-specific antibodies. We assessd the effect of Δ1–9-G129R-hPRL on the phpsphorylation of STAT5, STAT3 and p38. Then, we evaluated the effects of all those signaling inhibitors on GH3 cell apoptosis (TUNEL assay) and proliferation (BrdU incorporation). Together, our results suggest that PRL induces apoptosis through the activation of JAK2/STAT5 and p38 MAPK pathways, whereas its antiproliferative effect is mediated by JAK2/STAT5, JAK2/STAT3, and P38 MAPK pathways.

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