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ATF3 is a member of the bZip transcription factor family that is ubiquitously upregulated at the transcriptional level during cellular responses to a variety of stressors. ATF3 appears to be a direct transcriptional target of p53, and DNA damage induced by BPDE treatment or UV irradiation results in a transient 8-10-fold increase in ATF3 mRNA in several cell types. However, the role of ATF3 in the DNA damage response is unclear. As one approach to a better functional understanding of ATF3, transgenic mice that overexpress human ATF3 in basal epithelial cells under the control of a bovine keratin 5 (K5) promoter have been generated. BK5.ATF3 mice express an easily observable sparse hair phenotype. Beginning as early as P7, hyperplastic changes in the K5-expressing, outer root sheath cells of the hair follicle can be observed. This hyperplasia results in multiple layers of outer root sheath cells in the mature follicle and large aberrantly shaped follicles. In contrast, the morphology of the inner root sheath is relatively unaffected. This is in agreement with the expression pattern of keratin K5, and hence expression of human ATF3. Strikingly, the transgenic hair follicles are unable to enter the catagen phase of the hair cycle, and remain large and anagen-like throughout adult life. The interfollicular epidermis of adult transgenic mice exhibits scattered regions of mild hyperplasia, and a generalized expression of keratin K6 becomes more prominent with age. Despite this chronic hyperplasia, no epidermally-derived tumors have been identified in BK5.ATF3 mice observed for 16 months. In contrast, a high incidence of lesions of the oral cavity, including squamous carcinomas, was seen in sagittal sections of the head obtained from BK5.ATF3 mice at necropsy at 16 months.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]