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 using the promoter of the interstitial retinol-binding protein (IRBP) gene. This gene becomes active prior to the terminal differentiation of photoreceptors. Because T antigen-transforming activity is attributable, at least in part, to the inactivation of the retinoblastoma (pRb) and 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 inactivate pRb in photoreceptors while leaving p53 intact. Rather than developing retinoblastomas, the retinas of these mice degenerate due to photoreceptor 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 this model, because mice expressing E7 in a p53 nullizygous background develop retinal tumors instead of undergoing retinal degeneration.
Howes
K A
KA
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio 87284.
Ransom
N
N
Papermaster
D S
DS
Lasudry
J G
JG
Albert
D M
DM
Windle
J J
JJ
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics; D017209:Apoptosis; D001483:Base Sequence; D003433:Crosses, Genetic; D004249:DNA Damage; D004195:Disease Models, Animal; D005134:Eye Neoplasms / Q000209:etiology / Q000235:genetics*; D005136:Eye Proteins; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D010786:Photoreceptor Cells / Q000254:growth & development* / Q000473:pathology; D012333:RNA, Messenger / Q000302:isolation & purification; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012160:Retina / Q000473:pathology; D012175:Retinoblastoma / Q000209:etiology / Q000235:genetics*; D012177:Retinol-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000099214:Retinol-Binding Proteins, Interstitial
D000957:Antigens, Viral, Tumor; D005136:Eye Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D012177:Retinol-Binding Proteins; D016159:Tumor Suppressor Protein p53; D000099214:Retinol-Binding Proteins, Interstitial; C059731:oncogene protein E7, Human papillomavirus type 16