RRC ID 52080
Author Mori J, Tanikawa C, Ohnishi N, Funauchi Y, Toyoshima O, Ueda K, Matsuda K.
Title EPSIN 3, A Novel p53 Target, Regulates the Apoptotic Pathway and Gastric Carcinogenesis.
Journal Neoplasia
Abstract BACKGROUND & AIM:p53 activation by cellular stresses induces the transcription of hundreds of its target genes. To elucidate the entire picture of its downstream pathway, we screened a cDNA microarray dataset of adriamycin-treated HCT116 p53-/- or p53+/+ cells and identified EPSIN 3 as a novel p53 target.
METHODS:Potential p53 binding sequences in the EPSIN 3 locus were evaluated by reporter and CHIP assays. To investigate the role of EPSIN 3 in the p53 downstream pathway, we assessed DNA damage-induced apoptosis in EPSIN 3-knockdown HCT116 cells or Epsin 3-deficient mice. In addition, we evaluated EPSIN 3 expression levels in various tissues, including gastric adenocarcinoma, human gastric mucosa with or without Helicobacter pylori infection, and mouse acute gastritis tissues induced by indomethacin.
RESULTS:In response to DNA damage, p53 induced the expression of EPSIN 3 through the p53 binding elements in the EPSIN 3 promoter and the first intron. Knockdown of EPSIN 3 resulted in resistance to DNA damage-induced apoptosis both in vitro and in vivo. EPSIN 3 expression was down-regulated in gastric cancer tissues compared with normal tissues. In addition, Helicobacter pylori infection and indomethacin-induced acute gastritis repressed EPSIN 3 expression in gastric mucosa.
CONCLUSIONS:EPSIN 3 is a novel p53 target and a key mediator of apoptosis. Chronic or acute mucosal inflammation as well as p53 inactivation induced down-regulation of EPSIN 3 and subsequently caused apoptosis resistance, which is a hallmark of cancer cells.
Volume 19(3)
Pages 185-195
Published 2017-3-1
DOI 10.1016/j.neo.2016.12.010
PII S1476-5586(16)30151-8
PMID 28152424
PMC PMC5288315
MeSH Adaptor Proteins, Vesicular Transport / genetics* Apoptosis / genetics* Cell Line Cell Proliferation Cell Transformation, Neoplastic / genetics* Cell Transformation, Neoplastic / metabolism* Gastritis / genetics Gastritis / metabolism Gastritis / microbiology Gastritis / pathology Gene Expression Regulation, Neoplastic Gene Knockout Techniques HCT116 Cells Humans Protein Binding Proteolysis Signal Transduction* Stomach Neoplasms / genetics* Stomach Neoplasms / metabolism* Stomach Neoplasms / pathology Stress, Physiological Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism*
IF 5.696
Times Cited 7
Resource
Human and Animal Cells 293T(RCB2202)