ABSTRACT
Although
the human papillomavirus (HPV) E7 oncogene is known to contribute to
the development of human cervical cancer, the mechanisms of its
carcinogenesis are poorly understood. The first identified and most
recognized function of E7 is its binding to and inactivation of the
retinoblastoma tumor suppressor (pRb), but at least 18 other biological
activities have also been reported for E7. Thus, it remains unclear
which of these many activities contribute to the oncogenic potential of
E7. We used a Cre-lox system to abolish pRb expression in
the epidermis of transgenic mice and compared the outcome with the
effects of E7 expression in the same tissue at early ages. Mice lacking
pRb in epidermis showed epithelial hyperplasia, aberrant DNA synthesis,
and improper differentiation. In addition, Rb-deleted
epidermis (i.e., epidermis composed of cells with Rb
deleted) exhibited centrosomal abnormalities and failed to
arrest the cell cycle in response to ionizing radiation. Transgenic
mice expressing E7 in skin display the same range of phenotypes. In
sum, few differences were detected between Rb-deleted
epidermis and E7-expressing epidermis in young mice. However, when both
E7 was expressed and Rb was deleted in the same tissue,
increased hyperplasia and dysplasia were observed. These findings
indicate that inactivation of the Rb pathway can largely account for
E7's phenotypes at an early age, but that pRb-independent
activities of E7 are detectable in
vivo.
Squamous epithelial hyperplasia and carcinoma in mice transgenic for the human papillomavirus type 16 E7 oncogene.