IDENTIFICATION OF NOVEL MOLECULAR SIGNALING PATHWAYS WHICH PROMOTES INVASIVE CANCER REGULATED BY TRANSFORMING GROWTH FACTOR BETA AND THE UBIQUITIN LIGASE TRAF6

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https://umu.diva-portal.org/smash/project.jsf?pid=project:1200

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Title [sv]

NYA MOLEKYLÄRA SIGNALERINGSVÄGAR SOM LEDER TILL INVASIV CANCER STYRS AV TRANSFORMING GROWTH FACTOR BETA OCH UBIQUITIN-LIGASET TRAF6

Title [en]

IDENTIFICATION OF NOVEL MOLECULAR SIGNALING PATHWAYS WHICH PROMOTES INVASIVE CANCER REGULATED BY TRANSFORMING GROWTH FACTOR BETA AND THE UBIQUITIN LIGASE TRAF6

Abstract [sv]

We will study the function of the ubiquitin-ligase TRAF6/serine-threonine kinase; TGFB type I receptor (TBRI) complex, in cancer cells. TRAF6 specify intracellular routing and function of TBRI, via Lys63-linked polyubiquitin chains. This post-translational modification promotes TBRI proteolytic cleavage, via TRAF6-induced activation of specific cutting enzymes, generating a liberated intracellular domain (ICD), which enters the nucleus. We will study the role TRAF6/TBRI-ICD to regulate transcription (have TRAF6 and TBRI enzymatic activity in the nucleus? is TBRI-ICD acting as a transcription factor?), migration and invasion of cancer cells. We will study if monoclonal antibodies (mabs; designed by us), which prevent cleavage of TBRI, can be used as novel cancer drugs to inhibit invasion/metastasis. We will investigate novel functions of Smad7, which binds to TBRI, for its activity in Wnt-induced responses and as a transcription factor (identified by us), to regulate activity of oncogenes, i.e c-Jun and HDAC6, and their role in tumor progression. We will use conventional biochemical, cell and molecular biology methods, as well as advanced confocal imaging, animal models and tumor tissues, to explore biological functions of the TRAF6/TBRI-ICD and Smad7/DNA-complexes, in tumor progression. This original project is internationally leading and it will evaluate novel cancer drugs (mabs, inhibitors of the invasive pathway) and promote design of future cancer-specific drugs.

Principal InvestigatorLandström, Marene Umeå University

Coordinating organisation

Umeå University

Funder

Vetenskapsrådet

Period

2013-01-01 － 2016-12-31

National Category

Cell and Molecular BiologyCancer and OncologyMedical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)