APOPTOSIS OR RETINOBLASTOMA - ALTERNATIVE FATES OF PHOTORECEPTORS EXPRESSING THE HPV-16 E7 GENE IN THE PRESENCE OR ABSENCE OF P53

A transgenic mouse model for retinoblastoma was produced previously by directing SV40 T antigen expression to retinal photoreceptor cells us ing the promoter of the interstitial retinol-binding protein (IRBP) ge ne. This gene becomes active prior to the terminal differentiation of photoreceptors. Because T antigen-transforming activity is attributabl e, at least in part, to the inactivation of the retinoblastoma (pRb) a nd p53 tumor suppressor proteins, we addressed the role of p53 in the development of retinoblastoma in mice. Transgenic mice expressing HPV- 16 E7 under the control of the IRBP promoter were generated to inactiv ate pRb in photoreceptors while leaving p53 intact. Rather than develo ping retinoblastomas, the retinas of these mice degenerate due to phot oreceptor cell death at a time in development when photoreceptors are normally undergoing terminal differentiation. The dying cells exhibit the histological and ultrastructural features of apoptosis and contain fragmented DNA. p53 is required for the induction of apoptosis in thi s model, because mice expressing E7 in a p53 nullizygous background de velop retinal tumors instead of undergoing retinal degeneration.