Dataset Information

Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High-Affinity Bivalent Ligand.

ABSTRACT: The E6 oncoproteins of high-risk mucosal (hrm) human papillomaviruses (HPVs) contain a pocket that captures LxxLL motifs and a C-terminal motif that recruits PDZ domains, with both functions being crucial for HPV-induced oncogenesis. A chimeric protein was built by fusing a PDZ domain and an LxxLL motif, both known to bind E6. NMR spectroscopy, calorimetry and a mammalian protein complementation assay converged to show that the resulting PDZ-LxxLL chimera is a bivalent nanomolar ligand of E6, while its separated PDZ and LxxLL components are only micromolar binders. The chimera binds to all of the hrm-HPV E6?proteins tested but not to low-risk mucosal or cutaneous HPV?E6. Adenovirus-mediated expression of the chimera specifically induces the death of HPV-positive cells, concomitant with increased levels of the tumour suppressor P53, its transcriptional target p21, and the apoptosis marker cleaved caspase?3. The bifunctional PDZ-LxxLL chimera opens new perspectives for the diagnosis and treatment of HPV-induced cancers.

SUBMITTER: Ramirez J

PROVIDER: S-EPMC4512291 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High-Affinity Bivalent Ligand.

Ramirez Juan J Poirson Juline J Foltz Clémence C Chebaro Yassmine Y Schrapp Maxime M Meyer Amandine A Bonetta Anaëlle A Forster Anne A Jacob Yves Y Masson Murielle M Deryckère François F Travé Gilles G

Angewandte Chemie (International ed. in English) 20150527 27

The E6 oncoproteins of high-risk mucosal (hrm) human papillomaviruses (HPVs) contain a pocket that captures LxxLL motifs and a C-terminal motif that recruits PDZ domains, with both functions being crucial for HPV-induced oncogenesis. A chimeric protein was built by fusing a PDZ domain and an LxxLL motif, both known to bind E6. NMR spectroscopy, calorimetry and a mammalian protein complementation assay converged to show that the resulting PDZ-LxxLL chimera is a bivalent nanomolar ligand of E6, wh ...[more]

PMID: 26014966

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Project description:Cervical cancer is a significant public health problem, especially in low- and middle-income countries, where women have little access to cervical cancer screening; consequently 80% of cervical cancer related mortality occurs in these regions. The development of screening methods that need less infrastructure thus represents an urgent medical need. The study aims to compare the detection rates of high-risk human papillomavirus 16 and 18 E6 oncoprotein in urine, vaginal self-collected, and cervical scrapes of women using the OncoE6™ Cervical Test and compare the HPV16 and/or HPV18 E6 detection rates with the HPV DNA testing. Paired urine, vaginal self-collected and cervical specimens were collected from 124 women who participated in cervical cancer screening or treatment in this proof-of-concept study and underwent to HPV16/18-E6 testing and high-risk HPV DNA testing prior to treatment of cervical neoplasia or cancer. Concordance between urinary, vaginal and cervical HPV16/18-E6 and HPV-DNA testing was evaluated for patients classified as negative group (<CIN2) and histological positive group (CIN2, CIN3 and invasive carcinoma). Overall, HPV16/18-E6 oncoprotein was detected in 30.6% of cervical samples, 20.3% of self-collected vaginal samples and 21% of urine samples. Regarding the clinical sensitivity, the HPV16/18-E6 oncoprotein was not detected in CIN2 cases, and was detected at low rates in CIN3 cases. The clinical sensitivity of the HPV16/18-E6 oncoprotein for detecting invasive cervical cancer was 70% for cervical scrapes, 55% for self-collected vaginal samples and 52% for urine samples. This study reports the urinary detection of E6 oncoprotein in vivo for the first time and our results suggest that this detection is only for invasive/microinvasive lesions. Then, further protocol development and standardization to achieve a clinical sensitivity for CIN2/3 detection close to what can be achieved for invasive lesions using the physician collected cervical is needed.

Dataset Information

Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High-Affinity Bivalent Ligand.

Publications

Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High-Affinity Bivalent Ligand.

Similar Datasets

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