1) エストロゲン(E)受容体の機能解析と抗老化分子SIRT1のE標的組織への作用に基いた新規ホルモン補充療法の開発に向けた研究(シンポジウム1:女性ヘルスケア「中高年に対する女性医学の展開」,第64回日本産科婦人科学会・学術講演会)

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Estrogens are used for the reduction of postmenopausal symptoms and for the preservation of bone mineral density, but recent epidemiological studies suggest that combined estrogen and progestogen hormone replacement therapy (HRT) possesses several detrimental effects. Some large cohort studies indicate that the frequency of breast cancer and ovarian cancer may increase by HRT. However, contrary to the carcinogenic properties of HRT, it appears to reduce the incidence of colorectal cancer. The use of HRT should be optimized according to the background and characteristics of its user, and tissue specific activities of estrogen. Most of the known actions of estrogen are mediated by estrogen receptor α(ERα) and ERβ, both of which bind 17β-Estradiol (E_2) and modulate transcription of E_2-responsive genes, and functional analysis of ER is crucial for the appropriate use of HRT. ERβ plays a multifaceted role in proliferation and differentiation of various cell types, and ERβ generally opposes the proliferative functions of ERα. Therefore, we believe that it is extremely important to investigate the physiological functions of ER and its co factors including BRCA1, a breast and ovarian caner suppressor known to suppress E_2-dependent transcriptional activation function of ERα. Recently, silent information regulator genes (Sirtuins) have been identified as targets of resveratrol. Sirtuin 1 (SIRT1) , originally found as an NAD^+-dependent histone deacetylase, is a principal modulator of pathways downstream of calorie restriction, and the activation of SIRT1 ameliorates glucose homeostasis and insulin sensitivity. BRCA1 has been shown to serve as a positive regulator of SIRT1 expression by binding to the promoter region of SIRT1. 1) To better understand the physiological roles of ERα and ERβ, the colon, the uterus, and the bladder of ERβ^<-/->7 mice were examined with respect to markers of proliferation and differentiation. Our results indicate that ERβ^<-/-> cells of the colonic, uterine, and bladder epithelia show increased proliferation and decreased differentiation, due to the loss of ERβ. 2) We have demonstrated that ERβ and DBC1 interact in living cells. We also have shown the direct interaction between amino-terminus of DBC1 and activation function-1/2 domain of ERβ by in vitro pull down assays. Although DBC1 shows no influence on the E_2-dependent transcriptional activation function of ERα, the expression of DBC1 negatively regulates the E_2-dependent transcriptional activation function of ERβ. SIRT1 also negatively regulates the E_2-dependent transcriptional activation function of ERβ similar to DBC1. 3) Tissue specific ER function was investigated by concomitant use of conjugated equine estrogen (CEE) and raloxifene (RAL) for patients with decreased bone mineral density. The subjects exhibited increased bone mineral density by the treatment of CEE plus RAL, and no detrimental side effects were observed by the treatment of CEE plus RAL. 4) Resveratrol is a naturally derived polyphenol known to possess phytoestrogenic properties. Resveratrol is known for its beneficial effects on energy homeostasis, and it also has multiple properties, including anti-oxidant, anti-inflammatory, and anti-tumor activities. Here we found that SIRT1 was localized in granulosa cells of the human ovary. The rat granulosa cells were treated with increasing doses of resveratrol, and resveratrol increased protein levels of SIRT1, LH receptor, StAR, and P450 aromatase. In addition, progesterone secretion was induced by the treatment of resveratrol. These results thus provide important implications to understand the mechanism of luteal defect. 5) The expression of SIRT1 was confirmed in uterine endometrium. We found that the expression of cell-adhesion molecule E-cadherin is dependent on SIRT1, thus we suggest the possibility that SIRT1 may function as a transcriptional factor in human endometrium. The pathophysiological function of SIRT1 in reproductive organs might open a new insight in gynecology, and these results further reinforce the principal role of estrogen in regulating tissue homeostasis and the importance of functional analysis of ER.
2012-10-01

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