Receptor Activator of NF-κB Ligand Induction via Jak2 and Stat5a in Mammary Epithelial Cells

Abstract

Prolactin (PRL) is the primary hormone that, in conjunction with local factors, leads to lobuloalveolar development during pregnancy. Recently, receptor activator of NF-B ligand (RANKL) has been identified as one of the effector molecules essential for lobuloalveolar development. The molecular mechanisms by which PRL may induce RANKL expression have not been carefully examined. Here we report that RANKL expression in the mammary gland is developmentally regulated and dependent on PRL and progesterone, whereas its receptor RANK (receptor activator of NF-B) and decoy receptor osteoprotegerin (OPG) are constitutively expressed at all stages in both normal (PRL ؉/؊ ) and prolactin knockout (PRL ؊/؊ ) mice. In vitro, PRL markedly increased RANKL expression in primary mammary epithelial cells and RANKL-luciferase reporter activity in CHOD6 cells, which constitutively express the PRL receptor. We identified a ␥-interferon activation sequence (GAS) in the region between residues ؊965 to ؊725 of the RANKL promoter, which conferred a PRL response. Using dominant negative mutants of recombinant Jak2 and Stat5 in CHOD6 cells, and by reconstituting the Jak2/Stat5 pathway in COS7 cells, we determined that Jak2 and Stat5a are essential for the PRL-induced RANKL expression in mammary gland.

DU145 human prostate cancer cells express functional receptor activator of NFκB: New insights in the prostate cancer bone metastasis process

“…However its expression is not restricted to this cell type, as it was also observed in other tissue including mammary gland [29], lung [20], brain [20], kidney [20] and hypertrophic chondrocytes [15]. Recently, functional RANK expression on tumor cells was reported by our laboratory [21] and others [22,30].…”

A Positive Feedback Loop of IL-21 Signaling Provoked by Homeostatic CD4+CD25− T Cell Expansion Is Essential for the Development of Arthritis in Autoimmune K/BxN Mice

“…How IL-21 induces RANKL expression remains unknown. Previously, IL-21-mediated signaling has been shown to activate Jak kinases and STAT transcription factors (5), and the RANKL promoter has been shown to bear an IFN-␥ activation sequence (GAS), a cis-element bound by STATs (38). This suggests that IL-21 signals may activate the RANKL promoter through Jak-STAT pathways and this possibility is currently under investigation.…”

Involvement of JAK2 and Src kinase tyrosine phosphorylation in human growth hormone-stimulated increases in cytosolic free Ca2+ and insulin secretion

“…Activation of JAK2 is essential for initiation of many biological actions of GH in cells (2,46). In pancreatic ␤-cells, GH-mediated proliferation is directly mediated via JAK2 activation (9).…”

“…Means Ϯ SE derived from 3 separate experiments for each are shown (*P Ͻ 0.05 for a chance difference by ANOVA). [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50], were cultured in RPMI 1640 tissue culture medium containing 10% (vol/vol) FBS, 100 IU/ml penicillin, and 100 g/ml streptomycin. The BRIN-BD11 ␤-cell line was established by electrofusion of RINm5F insulinoma cells with New England Deaconess Hospital (NEDH) rat pancreatic islet cells and shares the major features of normal pancreatic ␤-cells (35,36).…”