Distinct Signaling Pathways Mediate Stimulation of Cell Cycle Progression and Prevention of Apoptotic Cell Death by Estrogen in Rat Pituitary Tumor PR1 Cells

Abstract

Estrogens control cell growth and viability in target cells via an interplay of genomic and extragenomicpathways not yet elucidated. Here, we show evidence that cell proliferation and survival are differentially regulated by estrogen in rat pituitary tumor PR1 cells. Pico-to femtomolar concentrations of 17␤-estradiol (E2) are sufficient to foster PR1 cell proliferation, whereas nanomolar concentrations of the same are needed to prevent cell death that occurs at a high rate in these cells in the absence of hormone. Activation of endogenous (PRL) or transfected estrogen-responsive genes occurs at the same, higher concentrations of E2 required to promote cell survival, whereas stimulation of cyclin D3 expression and DNA synthesis occur at lower E2 concentrations. Similarly, the pure antiestrogen ICI 182,780 inhibits estrogen response element-dependent trans-activation and cell death more effectively than cyclin-cdk activity, G 1 -S transition, or DNA synthesis rate. In antiestrogen-treated and/or estrogen-deprived cells, death is due predominantly to apoptosis. Estrogeninduced cell survival, but not E2-dependent cell cycle progression, can be prevented by an inhibitor of c-Src kinase or by blockade of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathway. These data indicate the coexistence of two distinguishable estrogen signaling pathways in PR1 cells, characterized by different functions and sensitivity to hormones and antihormones.

Estrogen inhibits D2S receptor-regulated Gi3 and Gs protein interactions to stimulate prolactin production and cell proliferation in lactotropic cells

“…We used a well-characterized PRL-secreting PR1 cell line (Pastorcic et al 1995, Chun et al 1998, Caporali et al 2003. Previously, using these cells, we have made several stable transfectants expressing undetectable amount of DA D2 receptors (V cells), containing the recombinant D2L receptor (D2L cell) or D2S receptors (D2S cell) (Sarkar et al 2005, Radl et al 2011.…”

Selective Estrogen Receptor Down-Regulator and Selective Estrogen Receptor Modulators Differentially Regulate Lactotroph Proliferation

“…Both genomic and non-genomic effects of E2 have been reported in lactotrophs. Previous reports showed that ICI suppressed cell proliferation and affected ER expression in GH3 and PR1 cells [18], [19]. We conducted a detailed comparison of the effects of ICI, tamoxifen and raloxifene, in the absence of exogenous E2, on lactotroph proliferation and PRL production/release [20].…”

Mediation of Basic Fibroblast Growth Factor-Induced Lactotropic Cell Proliferation by Src-Ras-Mitogen-Activated Protein Kinase p44/42 Signaling

“…2E). U0126 has been also shown, by Caporali et al (24), to block MAPK activation in PR1 cells. The basal proliferation of PR1 cells, as determined by 3 .…”

“…It is interesting to note that the activation of prolactin gene expression by estradiol in PR1 and GH3 somatolactotroph cell lines is mediated by MAPK p44/42 but is independent of Src (46). However, estradiol-induced cell survival of PR1 cells uses an Src-MAPK p44/42-dependent pathway (24).…”

“…Like lactotropes, PR1 cells secrete prolactin and respond positively to bFGF and estradiol (6,24,25). Because lactotrope enrichment requires a large number of animals to get enough pituitaries, and because PR1 cells show a growth response to bFGF similar to that of lactotropes ( Fig.…”