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

Projektbeschreibung

Wie das humane Cytomegalovirus Krebs beeinflussen kann

Das humane Cytomegalovirus (HCMV) ist ein Herpesvirus, mit dem sich 80-100 % der Menschen in Europa infizieren. Bei gesunden Menschen treten nur wenige Symptome auf, aber neuere Erkenntnisse deuten darauf hin, dass möglicherweise ein Zusammenhang zwischen HCMV und Krebs sowie Herzerkrankungen besteht. Im Rahmen des EU-finanzierten Projekts ViHiHippo werden zur Untersuchung dieses Zusammenhangs zwei der viralen Proteine, US28 und UL78, untersucht, die das Signalnetzwerk der Wirtszelle, insbesondere den Hippo-Signalweg, unterwandern. Vorläufige Projektergebnisse deuten darauf hin, dass beide Proteine den Hippo-Signalweg unterwandern, allerdings auf unterschiedliche Weise. Die Forschenden werden biochemisch ermitteln, wie die einzelnen Rezeptorproteine funktionieren, und durch Protein-Knockout genau verstehen, wie das humane Cytomegalovirus Krebs beeinflussen kann.

Ziel

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.

Koordinator

STICHTING VU
Netto-EU-Beitrag
€ 187 624,32
Adresse
DE BOELELAAN 1105
1081 HV Amsterdam
Niederlande

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Region
West-Nederland Noord-Holland Groot-Amsterdam
Aktivitätstyp
Higher or Secondary Education Establishments
Links
Gesamtkosten
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