Prolactin (PRL)-PRL receptor system increases cell proliferation involvingJNK (c-jun amino terminal kinase) and AP-1 activation: Inhibition by glucocorticoids

PRL receptor (PRLR) signal transduction supports PRL-induced growth/differe ntiation processes. While PRL is known to activate Jak2-Stat5 (signal trans ducer and activator of transcription 5) signaling pathway, the mechanism by which cell proliferation is stimulated is less known. We show that PRL ind uces proliferation of bovine mammary gland epithelial cells and AP-1 site a ctivation, Using PRLR mutants and the PRLR short form, we have found that b oth homodimerization of PRLR wild type and the integrity of box-1 and C-dis tal tyrosine of PRLR intracellular domain are needed in PRL-induced prolife ration and AP-1 activation, The effect of PRL has been assayed in the prese nce of dexamethasone (Dex), insulin, and alone. We found that Dex negativel y regulates PRL-induced proliferation and AP-1 site activation. We demonstr ate that PRL exerts activation of AP-1 transcriptional complex, and the mec hanism by which this activation is produced is also studied. We show that P RL induces an increase in the c-Jun content of AP-1 transcriptional complex es. The PRL-induced c-Jun of AP-1 transcriptional complex diminishes in the presence of Dex in a dose-dependent manner. Dex inhibition was reversed by the higher concentration of PRL added to cells. Despite the fact that the regulation of the AP-1 site is complex, we found that PRL activates the c-J un amino terminal kinase (JNK), while glucocorticoid prevents this JNK acti vation, These data support a regulation of cellular growth by PRL-PRLR syst em by increasing AP-1 transcriptional complex activity via JNK activation. JNK activation can be repressed by glucocorticoid in a DNA-binding-independ ent manner.