TEMPORALLY DISTINCT PATTERNS OF P53-DEPENDENT AND P53-INDEPENDENT APOPTOSIS DURING MOUSE LENS DEVELOPMENT

Programmed cell death, or apoptosis, is a critical event in the develo pment of multicellular organisms, and its perturbation is implicated i n many diseases including cancer. The tumor suppressor protein p53 is known to mediate apoptosis induced by the DNA tumor virus oncoproteins , adenovirus E1A (AdE1A) and SV40 T antigen (SV40 Tag). We have recent ly demonstrated that the E6 and E7 oncoproteins of human papillomaviru s type 16 (HPV-16) modulate apoptosis when expressed in the lens of tr ansgenic mice. In this study we have identified the pathways that medi ate E7 induction and E6 inhibition of apoptosis during different stage s in the development of the lens. E7 transgenic mice made p53-null wer e only partially rescued in their apoptotic phenotype, indicating that both p53-dependent and -independent pathways mediate E7-induced apopt osis in the lens. The E6 transgene and p53-null genotype acted additiv ely to reduce levels of apoptosis induced by E7 in neonatal lenses, in dicating that E6 modulates apoptosis at least in part through p53-inde pendent mechanisms. The partial reduction in E7-induced apoptosis by t he p53-null genotype correlated with an increased incidence of lens tu mors in adult E7 transgenic mice. Analyses of embryonic lenses at E13. 5, E15.5, and E17.5 revealed a temporally distinct activation of p53-d ependent and -independent apoptosis in the E7 lens. During the early s tages of lens development, apoptosis was highly p53-dependent, whereas at later stages, apoptosis occurred through both p53-independent and -dependent pathways. This later time correlates temporally with the ti me of normal fiber cell denucleation, which can be inhibited by Eb thr ough a p53-independent mechanism. These data suggest a similarity betw een the mechanism regulating E7-induced, p53 independent apoptosis and the apoptotic-like developmental process of fiber cell denucleation, and the mechanisms through which E6 suppresses both processes.