ALTERED CELL-CYCLE REGULATION IN THE LENS OF HPV-16 E6 OR E7 TRANSGENIC MICE - IMPLICATIONS FOR TUMOR-SUPPRESSOR GENE-FUNCTION IN DEVELOPMENT

Tumor suppressor proteins are believed to play a role in regulating ce ll cycle control during mammalian development. The E6 and E7 oncoprote ins from human papillomavirus type 16 are known to affect cell growth control, at least in part, through their inactivation of cellular tumo r suppressor gene products, p53 and Rb, respectively. Therefore, these viral proteins can serve as trans-dominant repressors of tumor suppre ssor gene function. To study the potential role of p53 and Rb in murin e lens morphogenesis, we generated transgenic mice in which the expres sion of Eb or E7 was directed to the developing lens. Transgenic mice expressing E7 exhibited microphthalmia and cataracts, whereas transgen ic mice expressing E6 exhibited cataracts without noticeable microphth almia. Microscopic analysis of the lenses from neonatal and adult E7 t ransgenic mice revealed inhibition of lens fiber cell differentiation, induction of cell proliferation in spatially inappropriate regions of the lens, and apoptosis. Transgenic mice expressing a mutant E7 that is defective in Rb/pl07 binding exhibited normal eyes, suggesting that the activity of Rb and/or Rb-like proteins is required for the pertur bation of lens development and induction of apoptosis in E7 mice. Micr oscopic analysis of lenses from E6 neonatal and adult transgenic mice indicated the presence of nuclei in elongated fiber cells, suggesting that E6 inhibits lens fiber cell denucleation. Furthermore, expression of E6 inhibited the apoptotic-like DNA degradation observed in the le nses of nontransgenic 15.5-day embryos. In lenses from neonatal EbxE7 double transgenic mice, the level of apoptosis was reduced compared wi th that seen in lenses from neonatal E7 mice. In adult EbxE7 double tr ansgenic mice, lens tumors developed, whereas in E6 or E7 only transge nic mice, tumors did not. Taken together, these results point to speci fic roles in lens morphogenesis for Rb and p53 and to the necessity of these tumor suppressor gene products in regulating exit from the norm al cell division cycle in differentiating lens fiber cells.