Squamous Cell Tumors in Mice Heterozygous for a Null Allele of Atp2a2, Encoding the Sarco(endo)plasmic Reticulum Ca2+-ATPase Isoform 2 Ca2+Pump

• Published in: The Journal of biological chemistry 2001-07, Vol.276 (29), p.26737-26740
• Main Authors: Liu, Lynne H., Boivin, Gregory P., Prasad, Vikram, Periasamy, Muthu, Shull, Gary E.
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Calcium-Transporting ATPases - genetics; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - genetics; Heterozygote; Mice; Papilloma - enzymology; Papilloma - genetics; Sarcoplasmic Reticulum Calcium-Transporting ATPases
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C100275200

Mutations in the human ATP2A2gene, encoding sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), cause Darier disease, an autosomal dominant skin disease characterized by multiple keratotic papules in the seborrheic regions of the body. Mice with a single functional Atp2a2allele (the mouse homolog of ATP2A2) were shown previously to have reduced levels of SERCA2 in heart and mildly impaired cardiac contractility and relaxation. Here we show that aged heterozygous mutant (Atp2a2+/−) mice develop squamous cell tumors of the forestomach, esophagus, oral mucosa, tongue, and skin. Squamous cell tumors occurred in 13/14Atp2a2+/− mice but were not observed in age- and sex-matched wild-type controls. Hyperkeratinized squamous cell papillomas and carcinomas of the upper digestive tract were the most frequent finding among Atp2a2+/− mice, and many animals had multiple tumors. Western blot analyses showed that SERCA2 protein levels were reduced in skin and other affected tissues of heterozygous mice. The development of squamous cell tumors in agedAtp2a2+/− mice indicates that SERCA2 haploinsufficiency predisposes murine keratinocytes to neoplasia. These findings provide the first direct demonstration that a perturbation of Ca2+ homeostasis or signaling can serve as a primary initiating event in cancer.