Steroid hormone receptors function classically in the nucleus as transcription factors. However, recent data indicate that there are also non-nuclear subpopulations of steroid hormone receptors, including estrogen receptors (ERs), that mediate membrane-initiated signaling of unclear basis and significance. Here we have shown that an estrogen-dendrimer conjugate (EDC) that is excluded from the nucleus stimulates endothelial cell proliferation and migration via ERalpha, direct ERalpha-Galphai interaction, and endothelial NOS (eNOS) activation. Analysis of mice carrying an estrogen response element luciferase reporter, ER-regulated genes in the mouse uterus, and eNOS enzyme activation further indicated that EDC specifically targets non-nuclear processes in vivo. In mice, estradiol and EDC equally stimulated carotid artery reendothelialization in an ERalpha- and G protein-dependent manner, and both agents attenuated the development of neointimal hyperplasia following endothelial injury. In contrast, endometrial carcinoma cell growth in vitro and uterine enlargement and MCF-7 cell breast cancer xenograft growth in vivo were stimulated by estradiol but not EDC. Thus, EDC is a non-nuclear selective ER modulator (SERM) in vivo, and in mice, non-nuclear ER signaling promotes cardiovascular protection. These processes potentially could be harnessed to provide vascular benefit without increasing the risk of uterine or breast cancer. PMID:20577047
Non-nuclear Estrogen Receptor α Signaling Promotes Cardiovascular Protection but not Uterine or Breast Cancer Growth in Mice,Chambliss K.L, Wu Q., Oltmann S, Umetani M, Korach K.L., Thomas G.D., Mineo C., Yuhanna I.S., Kim S.H., Madak-Erdogan Z., Maggi A., Dineen S.P., Roland C.L., Brekken R.A., Katzenellenbogen J.A., Katzenellenbogen B.S., Shaul P.W., Journal of Clinical Investigation, 2010,120(7):2319:2330
By firstname.lastname@example.org on May 29, 2013 in Extra-nuclear Initiated Estrogen Receptor Signaling, Metabolism
- Non-Nuclear Estrogen Receptor Activation Improves Hepatic Steatosis in Female Mice.
- ERα-XPO1 crosstalk controls tamoxifen sensitivity in tumors by altering ERK5 cellular localization
- Estrogen and Microbiota Crosstalk: Should We Pay Attention?
- Nuclear and extranuclear-initiated estrogen receptor signaling crosstalk and endocrine resistance in breast cancer
- Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues
Estrogen Receptor Alpha Represses Transcription of Early Target Genes via p300 and CtBP1, Stossi F, Madak-Erdogan Z, Katzenellenbogen BS, Molecular and Cellular Biology. 2009 Apr;29(7):1749-59