Prolactin (PRL)-PRL receptor system increases cell proliferation involving JNK (c-Jun amino terminal kinase) and AP-1 activation: inhibition by glucocorticoids.

PRL receptor (PRLR) signal transduction supports PRL-induced growth/differentiation processes. While PRL is known to activate Jak2-Stat5 (signal transducer and activator of transcription 5) signaling pathway, the mechanism by which cell proliferation is stimulated is less known. We show that PRL induces proliferation of bovine mammary gland epithelial cells and AP-1 site activation. Using PRLR mutants and the PRLR short form, we have found that both homodimerization of PRLR wild type and the integrity of box-1 and C-distal tyrosine of PRLR intracellular domain are needed in PRL-induced proliferation and AP-1 activation. The effect of PRL has been assayed in the presence of dexamethasone (Dex), insulin, and alone. We found that Dex negatively regulates PRL-induced proliferation and AP-1 site activation. We demonstrate that PRL exerts activation of AP-1 transcriptional complex, and the mechanism by which this activation is produced is also studied. We show that PRL induces an increase in the c-Jun content of AP-1 transcriptional complexes. 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-Jun amino terminal kinase (JNK), while glucocorticoid prevents this JNK activation. These data support a regulation of cellular growth by PRL-PRLR system by increasing AP-1 transcriptional complex activity via JNK activation. JNK activation can be repressed by glucocorticoid in a DNA-binding-independent manner.