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

Hideaki Toki, Osamu Minowa, Maki Inoue, Hiromi Motegi, Yuko Karashima, Ami Ikeda, Hideki Kaneda, Yoshiyuki Sakuraba, Yuriko Saiki, Shigeharu Wakana, Hiroshi Suzuki, Yoichi Gondo, Toshihiko Shiroishi, Tetsuo Noda

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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 Ca2+-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.

Original languageEnglish
Pages (from-to)175-182
Number of pages8
JournalBiochemical and biophysical research communications
Volume476
Issue number4
DOIs
Publication statusPublished - 2016 Aug 5
Externally publishedYes

Keywords

  • Calcium ATPase
  • Darier disease
  • ENU mutagenesis
  • Endoplasmic reticulum
  • Squamous cell carcinoma
  • Tumor development

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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