Fiche publication
Date publication
mai 2015
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DERYCKERE Francois
,
Dr MASSON Murielle
,
Dr TRAVE Gilles
Tous les auteurs :
Ramirez J, Poirson J, Foltz C, Chebaro Y, Schrapp M, Meyer A, Bonetta A, Forster A, Jacob Y, Masson M, Deryckere F, Trave G
Lien Pubmed
Résumé
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.
Référence
Angew Chem Int Ed Engl. 2015 May 27
