SKIN-SPECIFIC EXPRESSION OF A TRUNCATED E1A ONCOPROTEIN BINDING TO P105-RB LEADS TO ABNORMAL HAIR FOLLICLE MATURATION WITHOUT INCREASED EPIDERMAL PROLIFERATION

In cultured cells, mutants of the Adenovirus Ela oncoprotein which bin d to a reduced set of cellular proteins, including p105-Rb, p107, and p60-cyclin A, are transformation defective but can still interrere wit h exogenous growth inhibitory and differentiating signals, such as tho se triggered by TGF-beta. We have tested the ability of one such mutan t, NTd1646, to interfere with keratinocyte growth and differentiation in vivo, in the skin of transgenic mice. Keratinocyte-specific express ion of the transgene was achieved by using a keratin 5 promoter. Two i ndependent lines of transgenic mice were obtained which expressed Ela specifically in their skin and exhibited an aberrant hair coat phenoty pe with striking regional variations. Affected hair shafts were short and crooked and hair follicles exhibited a dystrophic or absent inner root sheath. Interfollicular epidermis was normal, but its hyperplasti c response to acute treatment with TPA (12-O-tetradecanoylphorbol-13-a cetate) was significantly reduced. Primary keratinocytes derived from these animals were partially resistant to the effects of TPA and TGF-b eta. The rate of spontaneous or chemically induced skin tumors in the transgenic mice was not increased. Thus, expression of a transgene whi ch interferes with known negative growth regulatory proteins causes pr ofound disturbances of keratinocyte maturation into a highly organized structure such as the hair follicle but does not lead to increased an d/or neoplastic proliferation.