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Viral hijacking of the Hippo pathway - HCMV-encoded viral GPCRs US28 and UL78 differentially modulate the Hippo pathway in cancer.

Description du projet

Comment le cytomégalovirus humain peut-il affecter le cancer?

Le cytomégalovirus humain (CMVH) est un herpèsvirus qui infecte 80 à 100 % des personnes en Europe. Chez les personnes en bonne santé, il y a peu de symptômes, mais des données récentes indiquent qu’il pourrait y avoir des liens entre le CMVH et le cancer et les maladies cardiaques. Pour étudier cette association, le projet ViHiHippo, financé par l’UE, étudie deux des protéines virales, US28 et UL78, qui détournent le réseau de signalisation de la cellule hôte, en particulier la voie Hippo. Les résultats préliminaires du projet indiquent que les deux protéines détournent la voie Hippo, mais de manière différente. Les chercheurs identifieront biochimiquement le fonctionnement de chaque protéine réceptrice et utiliseront l’invalidation génique des protéines pour comprendre exactement comment le CMVH peut influencer le cancer.

Objectif

The human cytomegalovirus (HCMV) is a herpesvirus that infects large parts of the population, with a prevalence of 80-100% in Europe. In healthy individuals, HCMV infection usually induces little to no symptoms. However, recent findings indicate that HCMV might contribute to a variety of diseases, including cancer and heart disease, two of the leading causes of death in Europe. The aim of this project is to uncover how and why HCMV changes the progression of cancer. To achieve this, we will investigate two HCMV-encoded viral G protein-coupled receptors (vGPCRs), US28 and UL78. Like other viral proteins, these vGPCRs hijack the signaling network of the host cell. Specifically, US28 and UL78 modulate the Hippo pathway, which controls cell proliferation and organ growth. As dysregulation of the Hippo pathway has been linked to cancer, modulation of this pathway by these vGPCRs may be a crucial determinant of HCMV on cancer progression. Our preliminary findings show that US28 and UL78 activate distinct mechanisms to hijack the Hippo pathway. US28 couples to G proteins of the Gq/G12 family, which are known to lead to Hippo modulation. Conversely, UL78 does not signal to Gq/G12, and seems to hijack the Hippo pathway via a different, undescribed mechanism. Thus, we will use a combination of biochemical readouts to investigate the signaling of US28- and UL78-expressing cells, to identify the distinct signaling mechanisms by which each vGPCR hijacks the Hippo pathway. We will also investigate the outcomes of this Hippo pathway modulation in a viral cancer setting by infecting a glioblastoma cell line with HCMV strains that either encode or lack US28 or UL78. Our findings will contribute to a fundamental understanding of how HCMV can influence progression of cancer. Moreover, these studies might potentially identify a new mechanism linking GPCRs to cell proliferation. In the long term this project may lay the groundwork for the discovery of new cancer treatments.

Coordinateur

STICHTING VU
Contribution nette de l'UE
€ 187 624,32
Adresse
DE BOELELAAN 1105
1081 HV Amsterdam
Pays-Bas

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Région
West-Nederland Noord-Holland Groot-Amsterdam
Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
Aucune donnée