GLOMSKI, K.; HERRON, B.J.; PARKER, A.; KINNE, J.; SIRACUSA, L.; FISHER, J.; MITTLER, J.; ROBINSON, I.; The College of New Jersey; Wadsworth Center, Albany; Thomas Jefferson University, Philadelphia: A mutation in 14-3-3 sigma is responsible for the Repeated epilation (Er) phenotype in mice.

The study of aberrant development in epithelial tissue may provide insight into the process of tumorogenesis. In mice, the mutation Repeated epilation (Er) produces a phenotype in the heterozygote characterized by cyclic hair loss and a heightened predisposition to squamous cell carcinoma. The Er/Er genotype is lethal due to severe epithelial hyperplasia during embryonic development. In this study, we localized the gene responsible for the Er phenotype to a 900kb region on mouse chromosome 4 using high resolution mapping. Subsequent sequencing of candidate genes revealed the aberrant gene to be 14-3-3σ (σ), a posphorylation-dependent binding protein involved in controlling G1/S and G2/M cell cycle progression. Specifically, we demonstrated that the Er mutation is an insertion mutation residing in the coding region of σ, which results in the truncation of the open reading frame by approximately 20%. In many human epithelial cancers, σ has been found to be significantly down-regulated or absent, suggesting that σ is vital in responding to DNA damage. Interestingly, we found that X-ray irradiation of primary cells from Er/Er individuals elucidated a DNA damage response comparable to that of wild type cells, suggesting that the truncated version of σ remains biologically functional or that a σ-independent checkpoint exists within these cells. No known in vivo model of σ dysfunction has been characterized previously. We are currently attempting to produce σ-null mice, which we propose to use in studies that would provide insight into the potential of manipulating σ expression for use in cancer therapy.