Interaction with CBP/p300 enables the bovine papillomavirus type 1 E6 oncoprotein to downregulate CBP/p300-mediated transactivation by p53

Abstract

The E6 oncoprotein of bovine papillomavirus type 1 (BPV-1) can transform cells independently of p53 degradation. The precise mechanisms underlying this transformation are not yet completely understood. Here it is shown that BPV-1 E6 interacts with CBP/p300 in the same way as described for the E6 proteins of oncogenic human papillomaviruses. This interaction results in an inhibition of the transcriptional coactivator function of CBP/p300 required by p53 and probably by other transcription factors. The comparison of the CBP/p300-binding properties of BPV-1 E6 mutants previously characterized in transcription and transformation studies suggests (i) that the E6-CBP/p300 interaction may be necessary, but not sufficient, for cell transformation, and (ii) that the transcriptional activator function, inherent to the E6 protein, is not derived from forming a complex with CBP/p300.Bovine papillomavirus type 1 (BPV-1) causes fibropapillomas in its natural host (cattle), sarcoids in horses, nonproductive fibromas in rodents after experimental infection and foci in cell cultures like mouse c127 fibroblasts (Howley, 1996). As there is great interest in human papillomaviruses (HPVs) as a cause of genital cancer (International Agency for

Adenovirus E1A requires the yeast SAGA histone acetyltransferase complex and associates with SAGA components Gcn5 and Tra1

“…This modi®cation alters Tat function in stimulating transcription from viral long terminal repeats (Benkirane et al, 1998;Kiernan et al, 1999;Marzio et al, 1998). Other viral factors such as SV40 T-antigen, papilloma E6, HTLV Tax and KSHV vIRF have been shown to interact with cellular HAT activities (Bex et al, 1998;Eckner et al, 1996;Jayachandra et al, 1999;Patel et al, 1999;Zimmermann et al, 1999). In some cases a clear requirement for HAT activity has been demonstrated, but the coactivator functions of p300 or CBP or as yet uncharacterized functions of P/CAF could also be required by these viral activators.…”

Human papillomavirus type 16 E6 protein interacts with cystic fibrosis transmembrane regulator-associated ligand and promotes E6-associated protein-mediated ubiquitination and proteasomal degradation

“…Their C-terminal sequences are illustrated (Figure 4b). L50G, C66G/C136G and D120G mutants of HPV16 E6 have an intact PDZ-binding motif but have some structural defects in one or both zinc-finger motifs that affect E6's transforming effect (Kanda et al, 1991;Nakagawa et al, 1995;Zimmermann et al, 1999). The results demonstrated that HPV16 E6s, having a whole consensus sequence at their C-termini (wild type (wt), L50G, C66G/C136G, D120G and L151V), kept the binding capacity regardless of the integrity of zinc-finger motifs even though somewhat reduced affinity was shown in mutants, especially in L151V.…”

Enhancement of p53-dependent gene activation by the transcriptional coactivator Zac1

“…In fact, p53 activity, including its ability to bind DNA, has been shown to be regulated by a variety of covalent modi®cations and interactions with a variety of other proteins (May and May, 1999). When tumor viruses infect cells they often interfere with p53 activity directly or indirectly and thereby promote unregulated cellular and viral proliferation in order to enhance viral replication e ciency (Zimmermann et al, 1999). Thus, in cells infected by such viruses, the viral oncoproteins (such as the HPV E6 proteins) that target and suppress p53 activity become part of the complex regulatory axis that revolves around p53.…”

“…HPV E6 proteins inhibit p53 activity by multiple mechanisms:reduction of cellular p53 levels by speci®cally targeting p53 for degradation; and binding to p53 to prevent its binding to p53-responsive promoters (Thomas et al, 1999). In addition, E6 proteins are known to bind to and inhibit the activity of CBP and p300 which also serve as coactivators for p53 (Patel et al, 1999;Zimmermann et al, 1999). HeLa cells are known to contain very low levels of wild type p53 due to the E6-mediated degradation of p53 (Matlashewski et al, 1986).…”