Increased Mitogen-Activated Protein Kinase Kinase/Extracellularly Regulated Kinase Activity in Human Endometrial Stromal Fibroblasts of Women with Endometriosis Reduces 3′,5′-Cyclic Adenosine 5′-Monophosphate Inhibition of Cyclin D1

Michael C Velarde, Lusine Aghajanova, Camran Nezhat, Camran R Nezhat, Linda C Giudice
Endocrinology · 2009 · vol. 150(10) , pp. 4701–4712 · doi:10.1210/en.2009-0389 · PMID:19589865 · PMC2754675 · W2075694687
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Increased mitogen-activated protein kinase kinase/extracellularly regulated kinase activity in endometrial stromal fibroblasts from women with endometriosis impairs cAMP's inhibition of cyclin D1, contributing to persistent proliferation.

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Abstract

Endometriosis is characterized by endometrial tissue growth outside the uterus, due primarily to survival, proliferation, and neoangiogenesis of eutopic endometrial cells and fragments refluxed into the peritoneal cavity during menses. Although various signaling molecules, including cAMP, regulate endometrial proliferation, survival, and embryonic receptivity in endometrium of women without endometriosis, the exact molecular signaling pathways in endometrium of women with disease remain unclear. Given the persistence of a proliferative profile and differential expression of genes associated with the MAPK signaling cascade in early secretory endometrium of women with endometriosis, we hypothesized that ERK1/2 activity influences cAMP regulation of the cell cycle. Here, we demonstrate that 8-Br-cAMP inhibits bromodeoxyuridine incorporation and cyclin D1 (CCND1) expression in cultured human endometrial stromal fibroblasts (hESF) from women without but not with endometriosis. Incubation with serum-containing or serum-free medium resulted in higher phospho-ERK1/2 levels in hESF of women with vs. without disease, independent of 8-Br-cAMP treatment. The MAPK kinase-1/2 inhibitor, U0126, fully restored cAMP down-regulation of CCND1, but not cAMP up-regulation of IGFBP1, in hESF of women with vs. without endometriosis. Immunohistochemistry demonstrated the highest phospho-ERK1/2 in the late-secretory epithelial and stromal cells in women without disease, in contrast to intense immunostaining in early-secretory epithelial and stromal cells in those with disease. These findings suggest that increased activation of ERK1/2 in endometrial cells from women with endometriosis may be responsible for persistent proliferative changes in secretory-phase endometrium.

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Condition tags

endometriosis

MeSH descriptors

Cyclic AMP Cyclin D1 Endometriosis Endometrium Extracellular Signal-Regulated MAP Kinases Adult Bromodeoxyuridine Cell Proliferation Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Dependent Protein Kinases Cyclin D1 Cyclin D1 Endometriosis Endometriosis Endometrium Endometrium Extracellular Signal-Regulated MAP Kinases Female Fibroblasts

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Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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