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Title: Novel allelic mutations in murine Serca2 induce differential development of squamous cell tumors

Abstract

Dominant mutations in the Serca2 gene, which encodes sarco(endo)plasmic reticulum calcium-ATPase, predispose mice to gastrointestinal epithelial carcinoma [1–4] and humans to Darier disease (DD) [14–17]. In this study, we generated mice harboring N-ethyl-N-nitrosourea (ENU)-induced allelic mutations in Serca2: three missense mutations and one nonsense mutation. Mice harboring these Serca2 mutations developed tumors that were categorized as either early onset squamous cell tumors (SCT), with development similar to null-type knockout mice [2,4] (aggressive form; M682, M814), or late onset tumors (mild form; M1049, M1162). Molecular analysis showed no aberration in Serca2 mRNA or protein expression levels in normal esophageal cells of any of the four mutant heterozygotes. There was no loss of heterozygosity at the Serca2 locus in the squamous cell carcinomas in any of the four lines. The effect of each mutation on Ca{sup 2+}-ATPase activity was predicted using atomic-structure models and accumulated mutated protein studies, suggesting that putative complete loss of Serca2 enzymatic activity may lead to early tumor onset, whereas mutations in which Serca2 retains residual enzymatic activity result in late onset. We propose that impaired Serca2 gene product activity has a long-term effect on squamous cell carcinogenesis from onset to the final carcinoma stage through an as-yetmore » unrecognized but common regulatory pathway. -- Highlights: •Novel mutations in murine Serca2 caused early onset or late onset of tumorigenesis. •They also caused higher or lower incidence of Darier Disease phenotype. •3D structure model suggested the former mutations led to severer defect on ATPase. •Driver gene mutations via long-range effect on Ca2+ distributions are suggested.« less

Authors:
; ; ; ; ;  [1];  [2];  [3];  [4];  [2];  [5];  [3];  [6];  [1];  [7]
  1. Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), Tsukuba, Ibaraki (Japan)
  2. Technology and Development Team for Mouse Phenotype Analysis, Riken BRC, Tsukuba, Ibaraki (Japan)
  3. Mutagenesis and Genomics Team, Riken BRC, Tsukuba, Ibaraki (Japan)
  4. Department of Molecular Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi (Japan)
  5. Department of Biochemistry, Asahikawa Medical University, Asahikawa, Hokkaido (Japan)
  6. Mammalian Genetics Laboratory, National Institute of Genetics, Mishima, Shizuoka (Japan)
  7. (Japan)
Publication Date:
OSTI Identifier:
22598784
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 476; Journal Issue: 4; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CALCIUM IONS; CARCINOGENESIS; CARCINOMAS; DOMINANT MUTATIONS; ENDOPLASMIC RETICULUM; ESOPHAGUS; GENE MUTATIONS; GENES; KNOCK-OUT REACTIONS; MESSENGER-RNA; MICE; MUTAGENESIS; MUTANTS; PHENOTYPE; PROTEINS

Citation Formats

Toki, Hideaki, Minowa, Osamu, Inoue, Maki, Motegi, Hiromi, Karashima, Yuko, Ikeda, Ami, Kaneda, Hideki, Sakuraba, Yoshiyuki, Saiki, Yuriko, Wakana, Shigeharu, Suzuki, Hiroshi, Gondo, Yoichi, Shiroishi, Toshihiko, Noda, Tetsuo, E-mail: tnoda@jfcr.or.jp, and Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo. Novel allelic mutations in murine Serca2 induce differential development of squamous cell tumors. United States: N. p., 2016. Web. doi:10.1016/J.BBRC.2016.04.136.
Toki, Hideaki, Minowa, Osamu, Inoue, Maki, Motegi, Hiromi, Karashima, Yuko, Ikeda, Ami, Kaneda, Hideki, Sakuraba, Yoshiyuki, Saiki, Yuriko, Wakana, Shigeharu, Suzuki, Hiroshi, Gondo, Yoichi, Shiroishi, Toshihiko, Noda, Tetsuo, E-mail: tnoda@jfcr.or.jp, & Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo. Novel allelic mutations in murine Serca2 induce differential development of squamous cell tumors. United States. doi:10.1016/J.BBRC.2016.04.136.
Toki, Hideaki, Minowa, Osamu, Inoue, Maki, Motegi, Hiromi, Karashima, Yuko, Ikeda, Ami, Kaneda, Hideki, Sakuraba, Yoshiyuki, Saiki, Yuriko, Wakana, Shigeharu, Suzuki, Hiroshi, Gondo, Yoichi, Shiroishi, Toshihiko, Noda, Tetsuo, E-mail: tnoda@jfcr.or.jp, and Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo. Fri . "Novel allelic mutations in murine Serca2 induce differential development of squamous cell tumors". United States. doi:10.1016/J.BBRC.2016.04.136.
@article{osti_22598784,
title = {Novel allelic mutations in murine Serca2 induce differential development of squamous cell tumors},
author = {Toki, Hideaki and Minowa, Osamu and Inoue, Maki and Motegi, Hiromi and Karashima, Yuko and Ikeda, Ami and Kaneda, Hideki and Sakuraba, Yoshiyuki and Saiki, Yuriko and Wakana, Shigeharu and Suzuki, Hiroshi and Gondo, Yoichi and Shiroishi, Toshihiko and Noda, Tetsuo, E-mail: tnoda@jfcr.or.jp and Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo},
abstractNote = {Dominant mutations in the Serca2 gene, which encodes sarco(endo)plasmic reticulum calcium-ATPase, predispose mice to gastrointestinal epithelial carcinoma [1–4] and humans to Darier disease (DD) [14–17]. In this study, we generated mice harboring N-ethyl-N-nitrosourea (ENU)-induced allelic mutations in Serca2: three missense mutations and one nonsense mutation. Mice harboring these Serca2 mutations developed tumors that were categorized as either early onset squamous cell tumors (SCT), with development similar to null-type knockout mice [2,4] (aggressive form; M682, M814), or late onset tumors (mild form; M1049, M1162). Molecular analysis showed no aberration in Serca2 mRNA or protein expression levels in normal esophageal cells of any of the four mutant heterozygotes. There was no loss of heterozygosity at the Serca2 locus in the squamous cell carcinomas in any of the four lines. The effect of each mutation on Ca{sup 2+}-ATPase activity was predicted using atomic-structure models and accumulated mutated protein studies, suggesting that putative complete loss of Serca2 enzymatic activity may lead to early tumor onset, whereas mutations in which Serca2 retains residual enzymatic activity result in late onset. We propose that impaired Serca2 gene product activity has a long-term effect on squamous cell carcinogenesis from onset to the final carcinoma stage through an as-yet unrecognized but common regulatory pathway. -- Highlights: •Novel mutations in murine Serca2 caused early onset or late onset of tumorigenesis. •They also caused higher or lower incidence of Darier Disease phenotype. •3D structure model suggested the former mutations led to severer defect on ATPase. •Driver gene mutations via long-range effect on Ca2+ distributions are suggested.},
doi = {10.1016/J.BBRC.2016.04.136},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 476,
place = {United States},
year = {Fri Aug 05 00:00:00 EDT 2016},
month = {Fri Aug 05 00:00:00 EDT 2016}
}