Human papillomavirus type 16 E6 proteins with glycine substitution for cysteine in the metal-binding motif

Kanda, Tadahito; Watanabe, Shiro; Zanma, Soichi; Sato, Hironori; Furuno, Akemi; Yoshiike, Kunito

doi:10.1016/0042-6822(91)90523-e

Cited by 62 publications

(58 citation statements)

References 40 publications

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“…Both pro-and anti-apoptotic members of the bcl-2 family are thought to be pore-forming proteins, located in the nuclear, endoplasmic reticular and mitochondrial membranes (Chen-Leavy and Cleary, 1990;Hockenbery, et al, 1990;Krajewski et al, 1996). HPV E6 proteins, although frequently found in the nucleus, have also been localized to non-nuclear membranes (Grossman et al, 1989;Kanda et al, 1991;Chen et al, 1995;Sherman and Schlegel, 1996); thus Bak and HPV-18 E6 have been found in the same subcellular locations.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Bak-induced apoptosis by HPV-18 E6

1998

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Human papillomavirus (HPV) E6 proteins inhibit apoptosis in both p53-dependent and p53-independent manners. A key point in apoptosis is the regulation provided by the Bcl-2 family; and in dierentiating keratinocytes, in which HPV replicates, the Bak protein is highly expressed. We show that HPV-18 E6 will inhibit Bak-induced apoptosis and this is mediated by an interaction between the E6 and Bak proteins resulting in degradation of the Bak protein in vivo. We also show that Bak protein interacts with the ubiquitin ligase, E6AP, and that a mutant of Bak defective in E6AP binding is overexpressed in comparison with wild type. These studies suggest that Bak is probably the ®rst naturally occurring target of E6AP to be identi®ed.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Bak-induced apoptosis by HPV-18 E6

1998

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“…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.…”

Section: Cal Interacts With Hpv16 E6 In Vivomentioning

confidence: 99%

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

Jeong

Kim

et al. 2006

Oncogene

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The PDZ proteins such as hDLG, hScrib and MAGIs function as the membrane-associated protein scaffolds and have been shown to interact with the high-risk human papillomavirus (HPV) E6s. In this report, we identify a Golgi-associated PDZ protein, cystic fibrosis transmembrane regulator-associated ligand (CAL) as a cellular target of HPV16 E6 by the proteomic approach. The carboxy-terminal PDZ-binding motif of HPV16 E6 specifically interacts with the PDZ domain of CAL, and the interaction enhances proteasome-mediated degradation of CAL. HPV16 E6 interacts with CAL more strongly and degrades it better than HPV18 E6 owing to the more compatible PDZ-binding motif. CAL is ubiquitinated by the E6/E6-associated protein (E6AP) complex or by E6AP alone, albeit less efficiently, which indicates that it could be a normal target of E6AP. Although it downregulates CAL at the transcript level, small interfering RNA-induced depletion of HPV16 E6 in Caski cells stabilizes CAL at the protein level, suggesting that HPV16 E6 mediates the proteasomal degradation of CAL in HPV-positive cervical cancer cells. HPV16 E6 may tightly regulate the vesicular trafficking processes by interacting with CAL, and such a modification can contribute to the development of cervical cancer.

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“…Crook et al (1991) have shown that deletion of amino acids 106-110 reduces to 12 % and 10 % E6 binding to and degradation of p53, respectively. The relevance of this mutation, which has never been described in HPV-16 natural variants, for E6 transforming activity remains to be investigated ; only substitutions of Cys-66 and Cys-136 by glycine have been associated with a severe reduction in transforming activity (Kanda et al, 1991).…”

Section: 350 [T To G (Leu To Val)] and 419 [T To G (Cys Tomentioning

confidence: 99%