title: VentX trans-activates p53 and p16ink4a to regulate cellular senescence.
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.
authors.affiliation: Gastroenterology Division, the Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wu
authors.forename: Hong
authors.initials: H
authors.lastname: Gao
authors.forename: Weixiong
authors.initials: W
authors.lastname: Ke
authors.forename: Martin
authors.initials: M
authors.lastname: Hager
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
authors.forename: Zhenglun
authors.initials: Z
authors.lastname: Zhu
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; D016159:Tumor Suppressor Protein p53; C408346:VENTX protein, human