Protein E6 in High Risk Human Papillomaviruses
Human Papillomavirus (HPV) refers to a group of more than one hundred HPV high risk or low risk strains associated with a variety of conditions. Over fifty strains lead to genital infections, while others influence the development of various cancers, such as cervical, skin, etc. The combination of H...
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| Published in: | The FASEB journal Vol. 32; no. S1; p. 652.23 |
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| Main Authors: | , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
The Federation of American Societies for Experimental Biology
01-04-2018
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| Online Access: | Get full text |
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| Summary: | Human Papillomavirus (HPV) refers to a group of more than one hundred HPV high risk or low risk strains associated with a variety of conditions. Over fifty strains lead to genital infections, while others influence the development of various cancers, such as cervical, skin, etc. The combination of HPV E6/E7, hTERT, and Ki67 mRNA expression levels complement each other to diagnose lesions of the aforementioned cancers, specifically dealing with the cervix. All HPV strains share a common structure: circular, double stranded DNA encoding for eight open reading frames (ORF) surrounded by a non‐enveloped capsid. ORFs function to produce the E1‐E7 proteins needed for HPV replication (early region), L1‐L2 proteins that make up the capsid (late region), and replicate and transcribe viral DNA with the help of cis components (long control region). The E6, in particular, is an oncoprotein composed of polypeptides made up of 150 amino acids and a Cys‐X‐X‐Cys motif that allow for the formation of two zinc fingers. E6 and E7 recognize a number of host proteins by hijacking their cellular domain‐motif interaction networks. In the HPV‐16 and HPV‐18 strains, the E6 protein binds its amino and carboxyl terminal regions to a leucine‐rich sequence (LxxLL) within the cellular ubiquitin ligase, E6AP. This heterodimer degrades p53, a proapoptotic tumor suppressor, although the exact mode of assembly is unknown. Complete degradation potentially leads to oncogenesis in high‐risk HPV strains, as these transformed cells have lost their ability to arrest at the G1 checkpoint within their cell cycle and perform apoptosis. Aside from the E6‐E6AP heterodimer binding directly to p53, the E6 protein has other oncogenic functions, allowing it to bind to four general classes of other proteins, providing indirect pathways to degrade p53. Binding options include proteins involved in cell polarity and motility, tumor suppressors and inducers of apoptosis, transcriptional coactivators and DNA replication/repair factors. Regarding transcription coactivators, degradation of p53 transcriptional activity is possible, as seen by the targeting of p53 coactivator p300/CBP or yADA3. Given the mechanism of E6‐E6AP complex hindering p53's from carrying out normal function, E6 is an attractive target for therapies against cervical cancers. The Olathe North High School MSOE Center for BioMolecular Modeling SMART Team used 3‐D modeling and printing technology to examine structure‐function relationships of E6.
Support or Funding Information
SMART team is a joint venture between the Milwaukee School of Engineering and the Olathe School District's 21st century program Medical Professions Academy.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal. |
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| Bibliography: | Mentor: Dr. Jack Treml, PhD, University of Kansas Sponsors: C. Elniff, L.B. Fogt |
| ISSN: | 0892-6638 1530-6860 |
| DOI: | 10.1096/fasebj.2018.32.1_supplement.652.23 |