Crosstalk between the human papillomavirus E2 transcriptional activator and the E6 oncoprotein

Abstract

Human papillomaviruses are the causative agents of cervical cancer. Previous studies have shown that loss of the viral E2 protein during malignant progression is an important feature of HPV-induced malignancy due to the resulting uncontrolled expression of the viral oncoproteins E6 and E7. We now show however that the viral E2 and E6 proteins are both capable of regulating each other's activity. When coexpressed, E2 and E6 induce marked changes in the pattern of each other's expression, with preferential accumulation in nuclear speckles. The two proteins interact directly, resulting in changes in the substrate specificities of E6 and the biochemical activities of E2. Thus, while E6 efficiently degrades its PDZ domain-containing substrates in the absence of E2, this activity is greatly diminished when E2 is present. Likewise, E2 alone drives both viral DNA replication and viral gene expression. However, in the presence of E6, viral DNA replication is inhibited while the transcriptional activity of E2 is elevated. These studies define a far more complex pattern of interaction between E2 and E6 than was previously thought and redefines the possible consequences of loss of E2 with respect to uncontrolled E6 activity and consequent malignant progression.

Inhibition of HPV-16 E7 oncogenic activity by HPV-16 E2

“…In both the cases, cell extracts were separated into soluble and insoluble fractions (Grm et al, 2005) and protein levels were detected by western blot. As shown in Figure 4a, E7 alone is localized almost entirely within the soluble fraction of the cell and is completely lost when cells are pre-permeabilized.…”

“…One set of transfected cells was left untreated, whereas the other was treated with a pre-permeabilization buffer for 7 min (Araujo et al, 2005). In both cases, cell extracts were separated into soluble and insoluble fractions (Grm et al, 2005) and protein levels were detected by western blot using specific antibodies against E2 (as above) or E7 (ED17; Santa Cruz). (b) U2OS cells grown on coverslips were transfected in a parallel experiment.…”

Polymorphisms and Functional Analysis of the Intact Human Papillomavirus16 E2 Gene

“…DBD has been shown to bind to the DNA binding site on LCR and regulates several gene expressions such as HPVE6/E7 oncogenes and the host gene (IL-10 and telomerase) (BermudezMorales et al, 2008). In addition, DBD can also bind to viral and cellular proteins such as E6, Mdm-2 and PARP (Lee et al, 2002;Grm et al, 2005;Gammoh et al, 2009). The hinge region forms a flexible link between the TAD and DBD and has shown to interact with Sp1 (Zou et al, 2000).…”

High-Risk Human Papillomavirus and Colorectal Carcinogenesis

“…It is well known that high-risk HPV early proteins, including E5, E6, and E7 oncoproteins, increase cellular alteration and probably lead to HPV induced carcinogenesis [20,[71][72][73]. More specifically, the E5 oncoprotein interacts with EGF-R1 signaling pathways (MAP Kinase and P13K-Akt) and proapoptotic proteins [74][75][76]; and therefore, it can play an important role in cell transformation and tumor formation.…”

“…On the other hand, E6 and E7 of the high-risk HPV types, such as HPV16, are thought to work together in lesions caused by this virus, since, the two proteins are expressed from bicistronic mRNA [77] and initiated from the viral early promoter (p97). These proteins have functions that stimulate cell cycle progression and both can associate with regulators of the cell cycle [70,72,78].…”