Am. Pierce et al., DEREGULATED EXPRESSION OF E2F1 INDUCES HYPERPLASIA AND COOPERATES WITH RAS IN SKIN TUMOR-DEVELOPMENT, Oncogene, 16(10), 1998, pp. 1267-1276
In cell culture studies, overexpression of the E2F1 transcription fact
or has been shown to stimulate proliferation, induce apoptosis, and co
operate with an activated ras gene to oncogenically transform primary
rodent cells. To study the effect of increased E2F1 activity on epithe
lial growth and tumorigenesis in vivo, transgenic mice expressing E2F1
under the control of a keratin 5 (K5) promoter were generated. Expres
sion of E2F1 in the epidermis results in hyperplasia but does not inhi
bit terminal differentiation. In a transgenic line expressing high lev
els of E2F1, mice have decreased hair growth likely as a result of abe
rrant apoptosis in developing hair follicles. Coexpression of a cyclin
D1 transgene with E2F1 augments epidermal hyperplasia and further dis
rupts hair follicle development suggesting that hypophosphorylated Rb
antagonizes the proliferative and apoptotic-promoting activities of E2
F1. Finally, the E2F1 transgene is found to cooperate with a v-Ha-ras
transgene to induce skin tumors in double transgenic animals. These fi
ndings confirm that many of the activities ascribed to E2F1 through in
vitro studies can be reproduced in vivo and demonstrate for the first
time that deregulated E2F activity can contribute to tumor developmen
t.