scholarly journals Neonatal Estrogen Receptor β Is Important in the Permanent Inhibition of Epithelial Cell Proliferation in the Mouse Uterus

Endocrinology ◽  
2015 ◽  
Vol 156 (9) ◽  
pp. 3317-3328 ◽  
Author(s):  
Tadaaki Nakajima ◽  
Yuki Tanimoto ◽  
Masami Tanaka ◽  
Pierre Chambon ◽  
Hajime Watanabe ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Epithelial Cell ◽  
Kinase Inhibitor ◽  
Estrogen Receptor Α ◽  
Epithelial Cell Proliferation ◽  
Cyclin Dependent Kinase ◽  
Mouse Uterus ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Old Mice

Estrogen receptor α (ERα) plays a pivotal role in the mouse uterine and vaginal epithelial cell proliferation stimulated by estrogen, whereas ERβ inhibits cell proliferation. ERβ mRNA is expressed in neonatal uteri and vaginae; however, its functions in neonatal tissues have not been ascertained. In this study, we investigated the ontogenic mRNA expression and localization of ERβ, and its roles in cell proliferation in neonatal uteri and vaginae of ERβ knockout (βERKO) mice. ERβ mRNA and protein were abundant in the uterine and vaginal epithelia of 2-day-old mice and decreased with age. In uterine and vaginal epithelia of 2-day-old βERKO mice, cell proliferation was greater than that in wild-type animals and in uterine epithelia of 90- and 365-day-old βERKO mice. In addition, p27 protein, known as a cyclin-dependent kinase inhibitor, was decreased in the uteri of 90- and 365-day-old βERKO mice. Inhibition of neonatal ERs by ICI 182780 (an ER antagonist) treatment stimulated cell proliferation and decreased p27 protein in the uterine luminal epithelium of 90-day-old mice but not in the vaginal epithelium. These results suggest that neonatal ERβ is important in the persistent inhibition of epithelial cell proliferation with accumulation of p27 protein in the mouse uterus. Thus, suppression of ERβ function in the uterine epithelium during the neonatal period may be responsible for a risk for proliferative disease in adults.

scholarly journals Juxtacrine Activity of Estrogen Receptor α in Uterine Stromal Cells is Necessary for Estrogen-Induced Epithelial Cell Proliferation

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Wipawee Winuthayanon ◽  
Sydney L. Lierz ◽  
Karena C. Delarosa ◽  
Skylar R. Sampels ◽  
Lauren J. Donoghue ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Epithelial Cell ◽  
Stromal Cells ◽  
Estrogen Receptor Α ◽  
Epithelial Cell Proliferation

scholarly journals The AF-1 Activation Function of Estrogen Receptor α Is Necessary and Sufficient for Uterine Epithelial Cell Proliferation In Vivo

Endocrinology ◽  
2013 ◽  
Vol 154 (6) ◽  
pp. 2222-2233 ◽  
Author(s):  
Anne Abot ◽  
Coralie Fontaine ◽  
Isabelle Raymond-Letron ◽  
Gilles Flouriot ◽  
Marine Adlanmerini ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Epithelial Cell ◽  
Gene Transcription ◽  
Crucial Role ◽  
Estrogen Receptor Α ◽  
Epithelial Cell Proliferation ◽  
Wild Type

Abstract Estrogen receptor-α (ERα) regulates gene transcription through the 2 activation functions (AFs) AF-1 and AF-2. The crucial role of ERαAF-2 was previously demonstrated for endometrial proliferative action of 17β-estradiol (E2). Here, we investigated the role of ERαAF-1 in the regulation of gene transcription and cell proliferation in the uterus. We show that acute treatment with E2 or tamoxifen, which selectively activates ERαAF-1, similarly regulate the expression of a uterine set of estrogen-dependent genes as well as epithelial cell proliferation in the uterus of wild-type mice. These effects were abrogated in mice lacking ERαAF-1 (ERαAF-10). Four weeks of E2 treatment led to uterine hypertrophy and sustained luminal epithelial and stromal cell proliferation in wild-type mice, but not in ERαAF-10 mice. However, ERαAF-10 mice still presented a moderate uterine hypertrophy essentially due to a stromal edema, potentially due to the persistence of Vegf-a induction. Epithelial apoptosis is largely decreased in these ERαAF-10 uteri, and response to progesterone is also altered. Finally, E2-induced proliferation of an ERα-positive epithelial cancer cell line was also inhibited by overexpression of an inducible ERα isoform lacking AF-1. Altogether, these data highlight the crucial role of ERαAF-1 in the E2-induced proliferative response in vitro and in vivo. Because ERαAF-1 was previously reported to be dispensable for several E2 extrareproductive protective effects, an optimal ERα modulation could be obtained using molecules activating ERα with a minimal ERαAF-1 action.

p21WAF1 Control of Epithelial Cell Cycle and Cell Fate

2002 ◽  
Vol 13 (6) ◽  
pp. 453-464 ◽  
Author(s):  
Wendy C. Weinberg ◽  
Mitchell F. Denning
Keyword(s):  
Cell Cycle ◽  
Epithelial Cell ◽  
Cell Fate ◽  
Cell Biology ◽  
Kinase Inhibitor ◽  
Growth Arrest ◽  
Nuclear Antigen ◽  
Central Position ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor

As a broad-acting cyclin-dependent kinase inhibitor, p21WAF1 occupies a central position in the cell cycle regulation of self-renewing tissues such as oral mucosa and skin. In addition to regulating normal cell cycle progression decisions, p21WAF1 integrates genotoxic insults into growth arrest and apoptotic signaling pathways that ultimately determine cell fate. As a result of its complex interactions with cell cycle machinery and response to mutagenic agents, p21WAF1 also has stage-specific roles in epithelial carcinogenesis. Finally, a view is emerging of p21WAF1 as not merely a cyclin-dependent kinase inhibitor, but also as a direct participant in regulating genes involved in growth arrest, senescence, and aging, thus providing an additional layer of control over matters of the cell cycle. This review discusses these various roles played by p21WAF1 in cell cycle control, and attempts to relate these to epithelial cell biology, with special emphasis on keratinocytes. (Abbreviations used include the following: Brdu, 5-Bromo-2-deoxyuridine; cdk, cyclin-dependent kinase; EGF, epidermal growth factor; KIP, kinase inhibitor protein; PCNA, proliferating cell nuclear antigen; and TPA, 12-O-tetradecanoylphorbol-13-acetate.)

Myc Targets Cks1 To Provoke Proliferation and Lymphomagenesis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2618-2618
Author(s):  
Ulrich Keller ◽  
Jennifer B. Old ◽  
Jonas Nilsson ◽  
Lisa Nilsson ◽  
Kirsteen Maclean ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
Burkitt Lymphoma ◽  
Poor Prognosis ◽  
Transcriptional Activity ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Induced Apoptosis

Abstract Reduced levels of the cyclin dependent kinase inhibitor p27Kip1 connote poor prognosis in cancer. In human Burkitt lymphoma, and in pre-cancerous B cells and lymphomas arising in Eμ-Myc transgenic mice, p27Kip1 expression is markedly reduced. Furthermore, the Cks1 component of the SCFSkp2 complex that is necessary for p27Kip1 ubiquitylation and degradation, and to a lesser extent Skp2, are induced by Myc ex vivo and in Eμ-Myc B-cells and lymphomas, and up-regulation of CKS1 and SKP2 are hallmarks of Burkitt lymphoma. While loss of Skp2 has rather modest effects, the deletion of Cks1 in Eμ-Myc B-cells elevates p27Kip1 levels, reduces proliferation and delays lymphoma development. In contrast, Myc-induced apoptosis and transcriptional activity are not affected by Cks1 (or Skp2) loss. Therefore, Myc accelerates cell proliferation and promotes tumorigenesis through its ability to selectively induce Cks1.

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