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



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.



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.



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.
Laboratory of Clinical Genome sequencing, Department of Computational biology and medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Jinichi
J
Mori
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Chizu
C
Tanikawa
Project for Realization of Personalized Cancer Medicine, Genome Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Naomi
N
Ohnishi
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Yuki
Y
Funauchi
Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo, Japan.
Osamu
O
Toyoshima
Project for Realization of Personalized Cancer Medicine, Genome Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Koji
K
Ueda
Laboratory of Clinical Genome sequencing, Department of Computational biology and medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo, Tokyo, Japan; Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address: koichima@ims.u-tokyo.ac.jp.
Koichi
K
Matsuda
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D005756:Gastritis / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D006801:Humans; D011485:Protein Binding; D059748:Proteolysis; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; C434483:EPN3 protein, human; D016159:Tumor Suppressor Protein p53