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Temporally distinct patterns of p53-dependent and p53-independent apoptosis during mouse lens development
1Department of Anatomy, University of Wisconsin Medical School, Madison 53706, USA.
Abstract:
Programmed cell death, or apoptosis, is a critical event in the development of multicellular organisms, and its perturbation is implicated in 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 recently demonstrated that the E6 and E7 oncoproteins of human papillomavirus type 16 (HPV-16) modulate apoptosis when expressed in the lens of transgenic mice. In this study we have identified the pathways that mediate E7 induction and E6 inhibition of apoptosis during different stages in the development of the lens. E7 transgenic mice made p53-null were only partially rescued in their apoptotic phenotype, indicating that both p53-dependent and -independent pathways mediate E7-induced apoptosis in the lens. The E6 transgene and p53-null genotype acted additively to reduce levels of apoptosis induced by E7 in neonatal lenses, indicating that E6 modulates apoptosis at least in part through p53-independent mechanisms. The partial reduction in E7-induced apoptosis by the p53-null genotype correlated with an increased incidence of lens tumors in adult E7 transgenic mice. Analyses of embryonic lenses at E13.5, E15.5, and E17.5 revealed a temporally distinct activation of p53-dependent and -independent apoptosis in the E7 lens. During the early stages 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 time of normal fiber cell denucleation, which can be inhibited by E6 through a p53-independent mechanism. These data suggest a similarity between 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.
Insights
Human papillomavirus (HPV) oncoproteins E6 and E7 impact programmed cell death (apoptosis) in mouse lenses. E7 induces apoptosis via p53-dependent and -independent pathways, while E6 inhibits it, potentially through p53-independent mechanisms.
Area of Science:
- Molecular Biology
- Oncology
- Developmental Biology
Background:
- Programmed cell death (apoptosis) is crucial for multicellular development and implicated in diseases like cancer.
- Tumor suppressor protein p53 mediates apoptosis induced by viral oncoproteins.
- Human papillomavirus (HPV) oncoproteins E6 and E7 modulate apoptosis in the lens.
Purpose of the Study:
- To identify pathways mediating E7-induced apoptosis and E6-inhibition of apoptosis in developing mouse lenses.
- To investigate the role of p53 in E7-induced apoptosis and E6-mediated inhibition.
- To explore the correlation between apoptotic pathways, E6/E7 expression, and lens tumor development.
Main Methods:
- Utilized transgenic mice expressing HPV-16 E6 and/or E7 oncoproteins.
- Generated p53-null E7 transgenic mice to assess p53-dependent and -independent apoptosis.
- Analyzed embryonic lenses at different developmental stages (E13.5, E15.5, E17.5) for apoptotic phenotypes.
- Correlated apoptotic mechanisms with lens tumor incidence in adult mice.
Main Results:
- E7-induced apoptosis in the lens is mediated by both p53-dependent and -independent pathways.
- E6 transgene and p53-null genotype additively reduced E7-induced apoptosis in neonatal lenses, suggesting p53-independent E6 mechanisms.
- Partial rescue of E7-induced apoptosis in p53-null mice correlated with increased lens tumor incidence.
- Apoptosis in E7 lenses showed temporally distinct p53-dependent (early) and p53-dependent/independent (later) activation.
- E6 inhibited apoptosis during later lens development, coinciding with fiber cell denucleation, via a p53-independent mechanism.
Conclusions:
- E7-induced apoptosis in the lens involves both p53-dependent and -independent pathways, with the latter becoming more prominent later in development.
- E6 inhibits apoptosis, particularly during later lens development and fiber cell denucleation, through p53-independent mechanisms.
- The findings suggest a link between E7-induced p53-independent apoptosis, E6's inhibition of apoptosis, and the developmental process of fiber cell denucleation.