EPSIN 3, A Novel p53 Target, Regulates the Apoptotic Pathway and Gastric Carcinogenesis.

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.

• Authors: Jinichi Mori, Chizu Tanikawa, Naomi Ohnishi, Yuki Funauchi, Osamu Toyoshima, Koji Ueda, Koichi Matsuda
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 19 Issue 3 Pg. 185-195 (03 2017) ISSN: 1476-5586 [Electronic] United States
• PMID: 28152424 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Vesicular Transport
• EPN3 protein, human
• Tumor Suppressor Protein p53

Topics

• Adaptor Proteins, Vesicular Transport (genetics)
• Apoptosis (genetics)
• Cell Line
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics, metabolism)
• Gastritis (genetics, metabolism, microbiology, pathology)
• Gene Expression Regulation, Neoplastic
• Gene Knockout Techniques
• HCT116 Cells
• Humans
• Protein Binding
• Proteolysis
• Signal Transduction
• Stomach Neoplasms (genetics, metabolism, pathology)
• Stress, Physiological
• Tumor Suppressor Protein p53 (genetics, metabolism)