Novel role for RbAp48 in tissue-specific, estrogen deficiency-dependent apoptosis in the exocrine glands
Novel role for RbAp48 in tissue-specific, estrogen deficiency-dependent apoptosis in the exocrine glands
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DOI：
10.1128/mcb.26.8.2924-2935.2006
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发表时间：
2006-04-01
影响因子：
5.3
通讯作者：
Hayashi, Y
中科院分区：
文献类型：
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作者：
Ishimaru, N;Arakaki, R;Hayashi, Y
虽然雌激素缺乏小鼠外分泌腺的组织特异性细胞凋亡可能有助于自身免疫性外分泌病的发生，但导致组织特异性细胞凋亡的分子机制仍不清楚。在此，我们发现RbAp48过表达可诱导雌激素缺乏引起的外分泌腺中P53介导的细胞凋亡。RbAp48可诱导细胞快速凋亡，并伴有P53磷酸化(Ser9)和α-fodrin切割。通过小干扰RNA降低RbAp48的表达可抑制细胞凋亡。C57BL/6去卵巢(OVX)小鼠外分泌腺有明显的RbAp48表达并伴有细胞凋亡，而OVX雌激素受体α(-/-)、P53(-/-)和E2F-1(-/-)小鼠未见表达。事实上，RbAp48基因的转基因表达诱导了外分泌腺的细胞凋亡，但不会诱导其他器官的细胞凋亡。这些发现表明，雌激素缺乏通过RbAp48的过度表达启动P53介导的外分泌腺细胞的凋亡，并可能在绝经后妇女中施加基于性别的自身免疫性外分泌病的风险。
Although tissue-specific apoptosis in the exocrine glands in estrogen-deficient mice may contribute to the development of autoimmune exocrinopathy, the molecular mechanism responsible for tissue-specific apoptosis remains obscure. Here we show that RbAp48 overexpression induces p53-mediated apoptosis in the exocrine glands caused by estrogen deficiency. RbAp48-inducible transfectant results in rapid apoptosis with p53 phosphorylation (Ser9) and alpha-fodrin cleavage. Reducing the expression of RbAp48 through small interfering RNA inhibits the apoptosis. Prominent RbAp48 expression with apoptosis was observed in the exocrine glands of C57BL/6 ovariectomized (OVX) mice but not in OVX estrogen receptor alpha(-/-), p53(-/-), and E2F-1(-/-) mice. Indeed, transgenic expression of the RbAp48 gene induced apoptosis in the exocrine glands but not in other organs. These findings indicate that estrogen deficiency initiates p53-mediated apoptosis in the exocrine gland cells through RbAp48 overexpression and exerts a possible gender-based risk of autoimmune exocrinopathy in postmenopausal women.