Abstract
Cellular senescence has emerged as a critical tumor suppressive mechanism in recent years, but relatively little is known about how senescence occurs. Here, we report that secreted Frizzled-related protein 1 (SFRP1), a secreted antagonist of Wnt signaling, is oversecreted upon cellular senescence caused by DNA damage or oxidative stress. SFRP1 is necessary for stress-induced senescence caused by these factors and is sufficient for the induction of senescence phenotypes. We present evidence suggesting that SFRP1 functions as a secreted mediator of senescence through inhibition of Wnt signaling and activation of the retinoblastoma (Rb) pathway and that cancer-associated SFRP1 mutants are defective for senescence induction.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Cell Line, Tumor
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Cell Proliferation
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Cellular Senescence*
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DNA Damage
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Fibroblasts
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Gene Expression Regulation, Neoplastic
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mutation
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Oxidative Stress
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Promoter Regions, Genetic
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RNA Interference
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RNA, Small Interfering
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Retinoblastoma Protein / metabolism*
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Signal Transduction
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Wnt Proteins / antagonists & inhibitors*
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Wnt Proteins / genetics
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Wnt Signaling Pathway*
Substances
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Intercellular Signaling Peptides and Proteins
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Membrane Proteins
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RNA, Small Interfering
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Retinoblastoma Protein
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SFRP1 protein, human
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Wnt Proteins