Nuclear signaling and cancer (Team K. Zanier)
Past research activities of the team dealt with the study of human Papillomavirus (HPV)-induced tumorigenesis, with a focus on key viral-host interactions mediated by the HPV E6 and E7 oncoproteins. We have solved the 3D structure of a ternary complex consisting of HPV E6, the ubiquitin ligase E6AP and tumor suppressor p53 (Martinez-Zapien D. et al., Nature 2016). This complex is required for E6-mediated degradation of p53, which is a prominent and most investigated HPV oncogenic activity.
We have also characterized the interaction of HPV E6 protein with structural domain called PDZ domain, which are mainly found in proteins implicated in cellular junctions. In parallel, we have developed a cDNA library, which comprises 590 ORFs coding for effectors of the human ubiquitination system. The library is compatible for screening of protein-protein interactions using the Gaussia princeps luciferase complementation assay (GPCA) and has been employed to identify novel interactions of the HPV E6 and E7 proteins with the ubiquitination system.
The current research of the team focuses on the identification and structure-function characterization of regulatory protein-protein complexes of the p53 and Hippo tumor suppressor pathways. These two signaling pathways are of paramount importance in cancer prevention. One project analyses specific aspects of the cross-talk between members of the p53 family of proteins (i.e. p53 and its functional homologues p63 and p73) and effectors of the NF-kB pathway. A second project explores the Hippo pathway, a key regulator of organ size and tissue homeostasis. This pathway has been shown to be deregulated in many solid tumors and targeted by oncogenic viruses. This project focuses on the study of the interplay between YAP/TAZ effectors of the Hippo pathway and the HPV E6 and E7 oncoproteins.
Our projects are tackled using a multidisciplinary approach, which involves interactomics methods, biochemical and functional analyses (molecular and cellular biology) as well as structural characterization (by NMR spectroscopy or x-ray crystallography).