Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Annexin A5 / metabolism
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Apoptosis / genetics*
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Blotting, Western
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Caspases / analysis
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Cell Line, Tumor
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Estrogen Receptor alpha / deficiency*
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Estrogen Receptor alpha / genetics*
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Female
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Fluorescein-5-isothiocyanate
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Fluorescent Dyes
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HT29 Cells
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HeLa Cells
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Humans
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Immunohistochemistry
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Jurkat Cells
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microfilament Proteins / metabolism
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Microscopy, Confocal
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Organ Specificity
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Ovariectomy
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Phosphorylation
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RNA, Small Interfering / metabolism
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Retinoblastoma-Binding Protein 4
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Salivary Glands / physiology*
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / genetics
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U937 Cells
Substances
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Annexin A5
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Carrier Proteins
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Estrogen Receptor alpha
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Fluorescent Dyes
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Microfilament Proteins
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Nuclear Proteins
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RNA, Small Interfering
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Rbbp4 protein, mouse
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Retinoblastoma-Binding Protein 4
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Tumor Suppressor Protein p53
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fodrin
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Caspases
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Fluorescein-5-isothiocyanate