Abstract
Cell senescence is a process of irreversible arrest of cell proliferation and plays an important role in tumor suppression. Recent studies showed that Wnt inhibition is a trigger of cellular senescence. Using methods of reverse genetics, we recently identified VentX, a human homolog of the vertebrate Xenopus Vent family of homeobox genes, as a novel Wnt repressor and a putative tumor suppressor in lymphocytic leukemia. Here, we show that VentX is a direct transcriptional activator of p53-p21 and p16ink4a-Rb tumor suppression pathways. Ectopic expression of VentX in cancer cells caused an irreversible cell cycle arrest with a typical senescence-like phenotype. Conversely, inhibition of VentX expression by RNA interference ameliorated chemotherapeutic agent-induced senescence in lymphocytic leukemia cells. The results of our study further reveal the mechanisms underlying tumor suppression function of VentX and suggest a role of VentX as a potential target in cancer prevention and treatment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Blotting, Western
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Cell Line
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Cell Line, Tumor
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Cell Survival / genetics
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Cell Survival / physiology
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Cells, Cultured
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Cellular Senescence / genetics
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Cellular Senescence / physiology*
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Chromatin Immunoprecipitation
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
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Flow Cytometry
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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Lymphocytes / cytology
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Lymphocytes / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics
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Signal Transduction / physiology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Homeodomain Proteins
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Tumor Suppressor Protein p53
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VENTX protein, human