Temporally distinct patterns of p53-dependent and p53-independent apoptosis during mouse lens development.

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 EIA (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.

Absence of acute apoptotic response to genotoxic carcinogens in p53‐deficient mice is associated with increased susceptibility to azoxymethane‐induced colon tumours

“…The fate of the remaining wild-type p53 allele during subsequent steps in oncogenesis might also be important. While some have found that loss of the wild-type allele of p53 was correlated with attenuated apoptosis and accelerated tumour growth, 2,3 other studies have failed to reveal a major role for p53 in modulating apoptosis in tumour. 22 Almost half (40%) …”

“…1 Attenuated apoptosis and accelerated tumour growth correlate with loss of p53, suggesting that loss of p53-mediated apoptosis is the rate-limiting step in tumour progression. 2,3 Whether p53 is important in regulating genetic events early in oncogenesis, such as initiating mutations, is unclear.…”

p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro

“…There are other similar examples among viral oncoproteins and cellular oncogenes involved in cell death regulation. The adenovirus E1A, HTLV-1 Tax and human papilloma virus (HPV) E7 proteins stimulate cell proliferation and also cause apoptosis, by both p53-dependent and p53-independent mechanisms (Debbas and White, 1993); Pan and Griep, 1995;Teodoro et al, 1995;Yamada et al, 1994) and the transcriptional regulator E2 of HPV can trigger apoptosis independently of p53 transcriptional activity (Desaintes et al, 1997). Overexpression of c-myc can lead to apoptosis that requires a property intrinsic to p53 in serumstarved ®broblasts, but it may operate through p53-independent pathways in epithelial cells, or during lymphomagenesis (Hsu et al, 1995;Sakamuro et al, 1995;Wagner et al, 1994).…”

The bovine papillomavirus type 1 E6 oncoprotein sensitizes cells to tumor necrosis factor alpha-induced apoptosis

“…For example, adenovirus E1A-induced apoptosis can be counteracted by the adenovirus E1B 19 kDa and E1B 55 kDa proteins (Debbas and White, 1993;Rao et al, 1992). Similar to adenovirus E1A/E1B mediated apoptosis regulation, HPV 16 E6 inhibited E7-induced apoptosis in the developing ocular lens of transgenic mice (Pan and Griep, 1995). In our experiments TNF-induced apoptosis was similar in the BPV-1-transformed ID13 and parental C127 cell lines and substantially less than the E6 expressing cells.…”

“…The apparent inconsistency in determining the e ect of E6 on apoptosis could be due to experimental conditions. Some of the apoptosis modulatory e ects of E6 were proposed to represent a p53-independent function Pan and Griep, 1995;Steller et al, 1996). It is clear that high-risk E6 possesses p53-independent transforming potential.…”