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(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.
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), Tsukuba, Ibaraki, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Toki
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), Tsukuba, Ibaraki, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Minowa
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), Tsukuba, Ibaraki, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), Tsukuba, Ibaraki, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Motegi
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), Tsukuba, Ibaraki, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Karashima
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), Tsukuba, Ibaraki, Japan.
authors.forename: Ami
authors.initials: A
authors.lastname: Ikeda
authors.affiliation: Technology and Development Team for Mouse Phenotype Analysis, Riken BRC, Tsukuba, Ibaraki, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kaneda
authors.affiliation: Mutagenesis and Genomics Team, Riken BRC, Tsukuba, Ibaraki, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sakuraba
authors.affiliation: Department of Molecular Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Saiki
authors.affiliation: Technology and Development Team for Mouse Phenotype Analysis, Riken BRC, Tsukuba, Ibaraki, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Wakana
authors.affiliation: Department of Biochemistry, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Mutagenesis and Genomics Team, Riken BRC, Tsukuba, Ibaraki, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.affiliation: Mammalian Genetics Laboratory, National Institute of Genetics, Mishima, Shizuoka, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Shiroishi
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), Tsukuba, Ibaraki, Japan; Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo, Japan. Electronic address: tnoda@jfcr.or.jp.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
mesh_terms: D000483:Alleles; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D019656:Loss of Heterozygosity; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse
keywords: Calcium ATPase; Darier disease; ENU mutagenesis; Endoplasmic reticulum; Squamous cell carcinoma; Tumor development