Nuclear import pathways of human papillomavirus *E6 proteins

2005 2005

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Abstract (summary)

The E6 oncoprotein is of vital importance in the pathogenesis of human papillomavirus (HPV) induced genital disease. The E6 transforming protein is a key player in the development for both benign disease such as condylomata and malignant disease such as cervical carcinoma in those infected with HPV. Certain sub-types of HPV infections have been stratified as low-risk and high-risk by epidemiologic studies, correlating with benign and malignant disease respectively. Our work characterizes the nuclear import of high-risk HPV16 E6 and explores differences in the nuclear import of E6 in high and low risk sub-types of HPVs.

The HPV16 E6 oncoprotein is imported into the nucleus via multiple pathways. Nuclear import in digitonin-permeabilized HeLa cells occurred when HPV16 E6 interacted with adapter karyopherin (Kap) α2 and entered the nucleus via the classical Kap α2β1 mediated pathway. Moreover, HPV16 E6 also localized to the nucleus in the presence of Kap β1 by itself or with Kap β2 (transportin). Binding of RanGTP to these Kap βs inhibited their interactions with the HPV16 E6 NLS (Nuclear Localization Signal).

Significantly, the NLS mutant E6R124G had reduced nuclear import activity while the E6 NLS deletion mutant, lacking 121KKQR 124, did not import at all. Thus, the HPV16 E6 oncoprotein interacts via its C-terminal NLS with several import receptors and enters the nucleus using multiple pathways.

The key difference in the nuclear import of the E6 protein associated with high and low risk HPV is active transport in high-risk types versus passive diffusion in low-risk types. Both high-risk HPV18 and 16 E6 are actively imported into the nucleus in the presence of either Kap β1 or Kap β2, in contrast with HPV11 E6 which does not interact with any of these import receptors. In the presence of Wheat Germ Agglutinin (WGA, inhibits active import) both high-risk HPV18 and 16 E6 remain cytoplasmic and show clear nuclear rim staining, indicating docking at the nuclear pore complex, but arrest of further transport into the nucleus. In contrast, low-risk HPV11 E6 showed similar low levels of diffusion mediated nuclear accumulation in both the presence and absence of WGA.

Indexing (details)

Molecular biology;
Cellular biology;
0307: Molecular biology
0379: Cellular biology
0992: Oncology
Identifier / keyword
Health and environmental sciences; Biological sciences; Cervical cancer; E6; HPV; Nuclear import
Nuclear import pathways of human papillomavirus *E6 proteins
Le Roux, Lucia G.
Number of pages
Publication year
Degree date
School code
DAI-B 66/01, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
0496953354, 9780496953356
Moroianu, Junona
Boston College
University location
United States -- Massachusetts
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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