Genomic and Nongenomic Effects of Estrogen Signaling in Human Endometrial Cells: Involvement of the Growth Factor Receptor Signaling Downstream AKT Pathway
S. C. J. P. GielenLindy A.M. SantegoetsLiesbeth C. KühneWilfred F. J. van IJckenB. Boers-SijmonsPayman Hanifi‐MoghaddamTheo J.M. HelmerhorstLeen J. BlokCurt W. Burger
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Mouse embryo cells with a targeted disruption of the insulin-like growth factor I receptor (IGF-IR) genes (R- cells) are refractory to transformation by the simian virus 40 large T antigen and/or an activated and overexpressed Ras, both of which readily transform cells from wild-type littermate embryos and other 3T3-like cells. R- cells are also refractory to transformation induced by overexpressed epidermal growth factor receptor and platelet-derived growth factor receptor beta. Since the platelet-derived growth factor receptor beta is required for transformation by bovine papillomavirus, we inquired whether the IGF-IR was also required for transformation by bovine papillomavirus E5 oncoprotein. We show here that R- cells are refractory to transformation by E5; reintroduction into R- cells of a human IGF-IR restores the susceptibility to transformation.
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Gliomas are primary tumor originated from the glial cells of the central nervous system, with the characteristics of unrestricted proliferation and widespread invasion to the surrounding normal brain tissue. The aberrant expression of the platelet-derived growth factor (PDGF) and its membrane receptor (PDGFR) activates the downstream signaling pathway, which affects the development of human glioma, but the molecular mechanisms remain unclear. PDGF and PDGFR play an important role in embryonic development and cell differentiation. PDGF-induced glioma animal model provides an important research method for the study of PDGF signaling pathway in the development of glioma. This article reviews the role of platelet-derived growth factor and its receptor in the development of glioma.
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The ratio of estrogen receptor beta (ERbeta) to ERalpha can alter the estrogen-like properties of tamoxifen. Transient transfection of ERbeta cDNA into cells can decrease the estrogen-like properties of the ERalpha:tamoxifen complex, whereas an increase in the amount of ERbeta is associated with tamoxifen-resistant breast cancer. We have addressed each of these hypotheses by examining well characterized laboratory models. We determined whether changes in endogenous ERbeta are responsible for the estrogen-like or antiestrogenic properties of tamoxifen or raloxifene in MDA-MB-231 cells transfected with cDNAs for ERalpha or mutants D351G, D351Y. We found that the amount of ERbeta mRNA in separate, stable transfectants of mutant ERalpha cDNA was always < 2% of ERalpha. Since at least a 50:50 mixture of ERalpha:ERbeta is needed to silence the tamoxifen:ERalpha complex, we conclude that insufficient ERbeta mRNA is available for selective ER modulation in stable transfectants of D351G and D351Y ERalpha. Similarly, to test the hypothesis that ERbeta is up-regulated and plays an important role during the development of tamoxifen-stimulated tumor growth, we quantitatively analyzed ERbeta and ERalpha mRNA in tamoxifen-naïve (MCF-7:E2, ECC1:E2) and tamoxifen-stimulated tumors (MCF-7:TAM, EnCa 101:TAM). We found that ERbeta mRNA levels were not significantly elevated in tamoxifen-stimulated tumors and the ERalpha mRNA remained over 99% out of all ER species for all the tumors tested. The same results were also obtained when mRNA levels of ERbeta and ERalpha in a series of tamoxifen-naïve and tamoxifen-resistant breast cancer was analyzed. We conclude that endogenous ERbeta may not play a dominant role in the modulation of the tamoxifen ERalpha complex, or in the development of tamoxifen-stimulated resistant tumor growth.
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Abstract R − cells are 3T3‐like cells derived from mouse embryos in which the insulin‐like growth factor I (IGF‐I) receptor (IGF‐IR) genes have been disrupted by targeted homologous recombination. These cells cannot grow in serum‐free medium supplemented by the growth factors that sustain the growth of other 3T3 cell lines, and cannot be transformed by oncogenes that easily transform wild type mouse embryo cells. We have used these cells to study the role of the IGF‐IR in the growth and transformation of cells overexpressing the platelet‐derived growth factor (PDGF)‐b̃b̃ receptor. We report that an overexpressed PDGF‐b̃b̃ receptor fails to induce mitogenesis or transformation in cells lacking the IGF‐IR, while capable of doing so in cells expressing the IGF‐IR. We conclude that the ability of the activated PDGF‐b̃b̃ receptor to stimulate cell proliferation and transformation requires a funcitional IGF‐IR. © 1995 Wiley‐Liss, Inc.
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