Abstract
Coactivator activator (CoAA) is a dual-functional coregulator that regulates steroid receptor-mediated transcription and alternative splicing. Previously, we have shown that CoAA has tumor-suppressive potential in tumorigenic human kidney cells. Here, we uncover a molecular mechanism by which Sjogren syndrome-associated autoantigen (SSA), an estrogen receptor (ER) coactivator, induces MYC oncogene by removing repressive CoAA through E2-dependent degradation of CoAA and promotes G(1)/S transition of the cell cycle as well as anchorage-independent growth capability of breast cancer cells. We also show that E2 and ER enhance the E3 ligase activity of SSA to modulate CoAA through splicing isoform-selective ubiquitylation. We propose this as one potential molecular basis for the reduced tumor incidence in autoimmune disease patients and suggest SSA as a potential therapeutic target to treat breast cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Breast / immunology
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Breast / metabolism
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Breast / pathology
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Breast Neoplasms / genetics*
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Breast Neoplasms / immunology*
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Breast Neoplasms / pathology
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Carcinogenesis / genetics
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Carcinogenesis / immunology
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Carcinogenesis / pathology
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Cell Cycle Checkpoints
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Cell Line
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Cell Line, Tumor
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Cell Proliferation
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Female
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Gene Expression Regulation, Neoplastic
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Genes, myc*
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Humans
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Intracellular Signaling Peptides and Proteins / immunology
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Intracellular Signaling Peptides and Proteins / metabolism
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Proteolysis
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Receptors, Estrogen / immunology*
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Ribonucleoproteins / immunology*
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Ubiquitin-Conjugating Enzymes / immunology
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Ubiquitin-Conjugating Enzymes / metabolism
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Ubiquitination
Substances
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Intracellular Signaling Peptides and Proteins
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RBM14 protein, human
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Receptors, Estrogen
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Ribonucleoproteins
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SS-A antigen
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Ubiquitin-Conjugating Enzymes