HUMAN KERATIN-1,BCL-2 TRANSGENIC MICE ABERRANTLY EXPRESS KERATIN-6, EXHIBIT REDUCED SENSITIVITY TO KERATINOCYTE CELL-DEATH INDUCTION, AND ARE SUSCEPTIBLE TO SKIN TUMOR-FORMATION

Nonmelanoma skin cancers (NMSC) are among the most common malignancies in the world. Typically, these neoplasms grow slowly and are comparat ively indolent in their clinical behavior. The most frequent molecular alterations implicated in the pathogenesis of these neoplasms involve genes known to be regulators of cell death including p53, Ha-ras and bcl-2. In order to evaluate the significance cell death deregulation d uring skin carcinogenesis, we generated a transgenic mouse model (HK1. bcl-2) using the human keratin 1 promoter to target the expression of a human bcl-2 minigene to the epidermis. Transgenic HK1.bcl-2 protein was expressed at high levels specifically in the epidermis extending f rom the stratum basale through the stratum granulosum. The epidermis o f HK1.bcl-2 mice exhibited multifocal hyperplasia without associated h yperkeratosis and aberrant expression of keratin 6. The rate of prolif eration was similar in HK1.bcl-2 and control epidermis although suprab asal BrdUrd incorporating cells were present only in HK1.bcl-2 skin, K eratinocytes from the HK1.bcl-2 mice mere significantly more resistant to cell death induction by U.V.-B, DMBA, and TPA, compared to central keratinocytes. Furthermore, papillomas developed at a significantly g reater frequency and shorter latency in the HK1.bcl-2 mice compared to control littermates following initiation with DMBA and promotion with TPA. Together these results support a role for bcl-2 in the pathogene sis of NMSC.