Opposing effects of bovine papillomavirus type 1 E6 and E7 genes on Fas-mediated apoptosis

Abstract

Programmed cell death (PCD), best exemplified by apoptosis, is a genetically programmed process of cellular destruction that is indispensable for normal development and homeostasis of multicellular organisms. Tumor necrosis factor a (TNF) and related cytokines are employed by host defenses to eliminate virally infected cells through induction of apoptosis. Many viruses have evolved specific gene products to modulate this process. We have recently shown that the bovine papillomavirus type 1 (BPV-1) E6 and E7 genes independently sensitize mouse cells to TNF-induced apoptosis. In this report, we investigated the effect of E6 and E7 expression on Fasmediated apoptosis. In contrast to TNF-mediated apoptosis, E6 and E7 demonstrated opposite effects: while E7 potentiated apoptosis triggered by an agonistic Fas antibody, E6 attenuated the effect. The mitochondrial pathway leading to the activation of caspases appears to be involved in Fas-mediated apoptosis in C127 cells. To further explore the mechanisms by which E6 and E7 modulate Fas-mediated apoptosis, we examined the surface expression of Fas in cells expressing E6 and E7. Significantly, levels of surface Fas expression correlated with the opposing effects of E6 and E7 on Fas-mediated apoptosis. Specifically, while E7 increased the surface expression of Fas, E6 reduced surface Fas expression. Mutational analysis demonstrated a correlation of E6's ability to downregulate surface Fas expression and apoptosis. Since the tumor suppressor p53 can be targeted for degradation by human papillomavirus and has been shown to induce apoptosis by upregulating surface Fas expression, we investigated the role of p53 in BPV-1 E6 and E7 modulation of Fas-mediated apoptosis. Our results demonstrated that the modulatory effects by E6 and E7 could occur in the absence of p53. Interestingly, the reduced Fas protein level on the cell surface is not accompanied by a decrease in total Fas levels in E6-expressing cells. Instead, considerably more Fas protein is found in the cytoplasm of cells expressing E6. These results highlight a novel activity of E6 and E7 that may be involved in viral pathogenesis.

Investigation of E2, E5, and E6 gene expression and DNA in situ fragmentation findings associated with progressive and regressive changes in benign neoplastic cutaneous lesions arising naturally from bovine papillomavirus-1 infection

“…However, some studies have demonstrated relationships between other E genes and apoptosis (16). To the best of our knowledge, previous reports have not mentioned bilateral trends in E gene expression with respect to progression and regression.…”

“…Accordingly, E5 expression is believed to play a role in promoting the growth of all tumor components from deep to surface layers. BPV-1 encodes E6 oncoproteins excepting E2 and E5 are the major transforming protein interacting with each other (16,21). E6 is another crucial factor in this transformation.…”

The human papillomavirus (HPV)-related cancer biology: An overview

“…This action promotes the p53 degradation [13,21,79,83]. Additionaly, the HPV-5 and 8 E6 oncoproteins interact with the CBP/ p300 complex [84][85][86], causing the TP53 downregulation by epigenetic mechanisms [87]. Furthermore, the E6 oncoprotein can interact with XRCC1 and O 6 -methylguanosine-DNA-methyltransferase proteins, which are recruited during the single-strand DNA break (SSB) repair [35], leading to cytogenetic damages [35] and neosis [88].…”

Papillomaviruses: a systematic review

“…, 2005; Liu and Baleja, 2008), which directs the p53 to 26S proteasome (Cai et al , 2013). The HPV-5 and 8 as well as BPV E6 oncoprotein interact with the CBP/p300 complex (Werness et al , 1990; Zimmermann et al , 2000; Liu et al , 2005), promoting p53 downregulation (Zimmermann et al , 1999). The loss of p53 contributes to genomic instability verified in cells infected by PVs (Araldi et al , 2013, 2015b), as well as in cells treated with BPV-1 E6 recombinant oncoprotein (Araldi et al , 2015a).…”

“…However, only BPV was able to infect the species (Koller and Olson, 1972). Due to its capability to infect different species and the pathogenic and morphological characteristics shared with HPV (Munday, 2014), BPV has been used as a prototype to study PV biology and oncology (Koller and Olson, 1972; Campo, 2002; Liu et al , 2005; Campo, 2006; Costa and Medeiros, 2014). Therefore, research involving BPV has contributed with the understanding of viral oncogenesis (Costa and Medeiros, 2014; Munday, 2014).…”