Meeting review: Extra-nuclear steroid receptors—Integration with multiple signaling pathways

Carbajal, Liliana; Deng, James; Dressing, Gwen E.; Hagan, Christy R.; Lange, Carol A.; Hammes, Stephen R.

doi:10.1016/j.steroids.2008.11.016

Cited by 2 publications

(1 citation statement)

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“…RU-486 mimics the effect of MPA regarding the expression of progestin-regulated proteins except for the expression of cyclin D1 and tissue factor at 1 9 10 -8 M To further corroborate our data suggesting the presence of agonistic effects of RU-486 and MPA, we evaluated the expression of several Pg-regulated proteins [47,48] after 24 h of treatment. RU-486 showed at low concentrations a similar pattern of protein expression regulation as MPA.…”

Section: Mpa and Ru-486 Activate Erksupporting

confidence: 61%

Classical membrane progesterone receptors in murine mammary carcinomas: agonistic effects of progestins and RU-486 mediating rapid non-genomic effects

Bottino

Cerliani

Rojas

et al. 2010

Breast Cancer Res Treat

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In this article, we demonstrate the expression of functional progesterone binding sites at the cell membrane in murine mammary carcinomas that are stimulated by progestins and inhibited by antiprogestins. Using confocal immunofluorescence, ligand binding and cell compartment-specific western blots, we were able to identify the presence of the classical progesterone receptors. Medroxyprogesterone acetate (MPA) and RU-486 (1 × 10(-11) and 1 × 10(-8) M) behaved as agonists activating extracellular signal-regulated kinases (ERKs) and progestin-regulated proteins, except for Cyclin D1 and Tissue factor which failed to increase with 1 × 10(-8) M RU-486, an experimental condition that allows PR to bind DNA. These results predicted a full agonist effect at low concentrations of RU-486. Accordingly, at concentrations lower than 1 × 10(-11) M, RU-486 increased cell proliferation in vitro. This effect was abolished by incubation with the ERK kinase inhibitor PD 98059 or by OH-tamoxifen. In vivo, at a daily dose of 1.2 μg/kg body weight RU-486 increased tumor growth, whereas at 12 mg/kg induces tumor regression. Our results indicate that low concentrations of MPA and RU-486 induce similar agonistic non-genomic effects, whereas RU-486 at higher concentrations may inhibit cell proliferation by genomic-induced effects. This suggests that RU-486 should be therapeutically administered at doses high enough to guarantee its genomic inhibitory effect.

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Section: Mpa and Ru-486 Activate Erksupporting

confidence: 61%

Classical membrane progesterone receptors in murine mammary carcinomas: agonistic effects of progestins and RU-486 mediating rapid non-genomic effects

Bottino

Cerliani

Rojas

et al. 2010

Breast Cancer Res Treat

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Genomic and Nongenomic Signaling Induced by 1α,25(OH)2-Vitamin D3 Promotes the Recovery of Amyloid-β Phagocytosis by Alzheimer's Disease Macrophages

Mizwicki

Menegaz

Zhang

et al. 2012

JAD

116

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Brain clearance of amyloid-β (Aβ42) by innate immune cells is necessary for maintenance of normal brain function. Phagocytosis of soluble Aβ42 by Alzheimer's disease (AD) macrophages is defective, recovered in all "Type I and Type II" AD patients by 1α,25(OH)2-vitamin D3 (1,25D3) and blocked by the nuclear vitamin D receptor (VDR) antagonist (23S)-25-dehydro-1α(OH)-vitamin D3-26,23-lactone (MK). Bisdemethoxycurcumin (BDC) is a VDR ligand and additive with 1,25D3 in promoting Aβ42 phagocytosis by Type I, but not by Type II macrophages. Here, we define the following intracellular mechanisms regulated by 1,25D3 that are associated with recovery of phagocytosis and consistent with the selectivity of BDC: 1) 1,25D3 potentiates a 4,4-diisothiocyanostilbene-2,2-disulfonic acid-sensitive chloride channel (i.e., ClC-3) currents in both Type I and II AD macrophages, but curcumin only potentiates the currents in Type I cells; 2) 1,25D3 is particularly effective in upregulating ClC-3 mRNA expression in Type II peripheral blood mononuclear cells (PBMCs) while both 1,25D3 and the BDC analog, C180, upregulate VDR mRNA, repressed by Aβ42 in Type II PBMCs; and 3) 1,25D3-induced Aβ42 phagocytosis is attenuated by the calcium-dependent ClC-3 blocker, inositol 3,4,5,6-tetraphosphate (IP4), in both AD Types and by the MEK1/2 inhibitor U0126 only in Type II macrophages. VDR hydrogen/deuterium exchange coupled mass spectrometry and computational results show differences between the abilities of 1,25D3 and curcuminoids to stabilize VDR helices associated with the regulation of gene transcription. The structure-function results provide evidence that 1,25D3 activation of VDR-dependent genomic and nongenomic signaling, work in concert to recover dysregulated innate immune function in AD.

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Meeting review: Extra-nuclear steroid receptors—Integration with multiple signaling pathways

Cited by 2 publications

References 0 publications

Classical membrane progesterone receptors in murine mammary carcinomas: agonistic effects of progestins and RU-486 mediating rapid non-genomic effects

Classical membrane progesterone receptors in murine mammary carcinomas: agonistic effects of progestins and RU-486 mediating rapid non-genomic effects

Genomic and Nongenomic Signaling Induced by 1α,25(OH)2-Vitamin D3 Promotes the Recovery of Amyloid-β Phagocytosis by Alzheimer's Disease Macrophages

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