The E7 oncoprotein of high-risk human papillomavirus type 16 enters the nucleus via a nonclassical Ran-dependent pathway

ABSTRACT We have recently identified E6TP1 (E6-targeted protein 1) as a novel high-risk human papillomavirus type 16 (HPV16) E6-binding protein. Importantly, mutational analysis of E6 revealed a strong correlation between the transforming activity and its abilities to bind and target E6TP1 for ubiquitin-mediated degradation. As a region within E6TP1 has high homology with GAP domains of known and putative Rap GTPase-activating proteins (GAPs), these results raised the possibility that HPV E6 may alter the Rap small-G-protein signaling pathway. Using two different approaches, we now demonstrate that human E6TP1 exhibits GAP activity for Rap1 and Rap2, confirming recent findings that a closely related rat homologue exhibits Rap-specific GAP activity. Using mutational analysis, we localize the GAP activity to residues 240 to 945 of E6TP1. Significantly, we demonstrate that coexpression of HPV16 E6, by promoting the degradation of E6TP1, enhances the GTP loading of Rap. These results support a role of Rap small-G-protein pathway in E6-mediated oncogenesis.

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Susceptibility of high-risk human papillomavirus type 16 to clinical disinfectants

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dku006 ◽

2014 ◽

Vol 69 (6) ◽

pp. 1546-1550 ◽

Cited By ~ 35

Author(s):

J. Meyers ◽

E. Ryndock ◽

M. J. Conway ◽

C. Meyers ◽

R. Robison

Keyword(s):

Human Papillomavirus ◽

High Risk ◽

Human Papillomavirus Type 16

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Stabilization and Functional Impairment of the Tumor Suppressor p53 by the Human Papillomavirus Type 16 E7 Oncoprotein

Virology ◽

10.1006/viro.2002.1375 ◽

2002 ◽

Vol 295 (1) ◽

pp. 74-85 ◽

Cited By ~ 48

Author(s):

Alexandra Eichten ◽

Matthew Westfall ◽

Jennifer A. Pietenpol ◽

Karl Münger

Keyword(s):

Human Papillomavirus ◽

Tumor Suppressor ◽

Functional Impairment ◽

Tumor Suppressor P53 ◽

E7 Oncoprotein ◽

Human Papillomavirus Type 16

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Human Papillomavirus Type 16 E7 Oncoprotein Associates with the Centrosomal Component γ-Tubulin

Journal of Virology ◽

10.1128/jvi.01669-07 ◽

2007 ◽

Vol 81 (24) ◽

pp. 13533-13543 ◽

Cited By ~ 37

Author(s):

Christine L. Nguyen ◽

Catherine Eichwald ◽

Max L. Nibert ◽

Karl Münger

Keyword(s):

Human Papillomavirus ◽

Gradient Centrifugation ◽

Sucrose Density Gradient ◽

Sucrose Density Gradient Centrifugation ◽

E7 Oncoprotein ◽

Human Papillomavirus Type 16 ◽

Retinoblastoma Tumor Suppressor ◽

Mitotic Abnormalities ◽

Small Pool ◽

Retinoblastoma Tumor

ABSTRACT Expression of a high-risk human papillomavirus (HPV) E7 oncoprotein is sufficient to induce aberrant centrosome duplication in primary human cells. The resulting centrosome-associated mitotic abnormalities have been linked to the development of aneuploidy. HPV type 16 (HPV16) E7 induces supernumerary centrosomes through a mechanism that is at least in part independent of the inactivation of the retinoblastoma tumor suppressor pRb and is dependent on cyclin-dependent kinase 2 activity. Here, we show that HPV16 E7 can concentrate around mitotic spindle poles and that a small pool of HPV16 E7 is associated with centrosome fractions isolated by sucrose density gradient centrifugation. The targeting of HPV16 E7 to the centrosome, however, was not sufficient for centrosome overduplication. Nonetheless, we found that HPV16 E7 can associate with the centrosomal regulator γ-tubulin and that the recruitment of γ-tubulin to the centrosome is altered in HPV16 E7-expressing cells. Since the association of HPV16 E7 with γ-tubulin is independent of pRb, p107, and p130, our results suggest that the association with γ-tubulin contributes to the pRb/p107/p130-independent ability of HPV16 E7 to subvert centrosome homeostasis.

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