Novel role for RbAp48 in tissue-specific, estrogen deficiency-dependent apoptosis in the exocrine glands.
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.
Ishimaru
Naozumi
N
Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3 Kuramotocho, Tokushima 770-8504, Japan.
Arakaki
Rieko
R
Omotehara
Fumie
F
Yamada
Koichi
K
Mishima
Kenji
K
Saito
Ichiro
I
Hayashi
Yoshio
Y
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000032:analysis; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D010052:Ovariectomy; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D056505:Retinoblastoma-Binding Protein 4; D012469:Salivary Glands / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D020298:U937 Cells; D013049:Spectrin
D017304:Annexin A5; D002352:Carrier Proteins; D020169:Caspases; D047628:Estrogen Receptor alpha; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D056505:Retinoblastoma-Binding Protein 4; D016159:Tumor Suppressor Protein p53; D013049:Spectrin; C489969:Rbbp4 protein, mouse