Novel Role for RbAp48 in Tissue-Specific, Estrogen Deficiency-Dependent Apoptosis in the Exocrine Glands

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 ␣-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 ␣ ؊/؊ , 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.

Pleiotropic Roles of the Msi1-Like Protein Msl1 in Cryptococcus neoformans

“…The CAF-1 complex is conserved from yeast to humans and consists of three proteins, Rlf2/Cac1, Cac2, and Msi1/ Cac3, which correspond to p150, p60, and p48, respectively, in human CAF-1. To form the CAF-1 complex, Cac2 and Msi1/Cac3 bind to the larger component Rlf2/Cac1, but there is no direct interaction between Cac2 and Msi1/Cac3 (19). Both the regulation and localization patterns of Msi1/Cac3 are distinct from those of Rlf2/ Cac1 and Cac2 (21,41), in accordance with the multiple functional roles of Msi1/Cac3.…”

“…Therefore, how Msi1 regulates the Ras/cAMP pathway in yeast remains elusive. Although Ras signaling is not mediated by cAMP in multicellular eukaryotes, an Msi1 homolog was also shown to antagonize Ras-mediated signaling in both Caenorhabditis elegans and humans (19,30,40). Furthermore, the overexpression of either RbAp48 or RbAp46, mammalian Msi1 homologs, suppresses the heat shock sensitivity of hyperactive Ras/ cAMP yeast mutants (36,37).…”

Novel homeodomain‐interacting protein kinase family member, HIPK4, phosphorylates human p53 at serine 9

“…Although phospho-p53 (Ser9) has been observed in several types of cells in response to UV, H 2 O 2 , adriamycin and TGF-b [6,8,12,28], there is little information about the function of Ser9 phosphorylation. We investigated the effect of HIPK4 over-expression on a synthetic p53 responsive element containing the promoter (2 · RE-tk-luc) and on two kinds of human p53-dependent gene promoter (BAX-luc and survivin-luc), using a luciferase assay in A549 cells, which express functional p53.…”

The enhancer of trithorax and polycomb gene Caf1/p55 is essential for cell survival and patterning in Drosophila development

“…Until now, mutant or reduced expression phenotypes of Caf1 homologs have been reported in yeast, Arabidopsis and C. elegans, but no mutations in Drosophila Caf1 have been identified and genetically characterized (Bouveret et al, 2006;Guitton and Berger, 2005;Hennig et al, 2003;Jullien et al, 2008;Lu and Horvitz, 1998;Ruggieri et al, 1989). Furthermore, reduced expression of the mammalian Caf1 homologs RbAp46 and RbAp48 is observed in human cancers, and in vitro studies suggest both genes may act as tumor suppressors, but the lack of Caf1 mouse models hinders our understanding of its potential role in human disease (Guan et al, 2001;Guan et al, 1998;Ishimaru et al, 2006;Kong et al, 2007;Li et al, 2003;Pacifico et al, 2007;Thakur et al, 2007). Chromatin remodeling adds a unique level of transcriptional regulation to the signaling pathways that control development by stably repressing genes in a heritable manner, and may therefore be of particular importance to genes and pathways that are re-used in development.…”