Project's Number: PSPB-094/2010
Title of project: The role of tumor susceptibility gene 101 (Tsg101) in transcriptional regulation in health and disease.
Person responsible for project (IIMCB): Professor Marta Miaczynska
Swiss partner: Department of Biochemistry Sciences II, University of Geneva (UNIGE)
Persons responsible for project (UNIGE): Professor Jean Gruenberg and Professor Marcos Gonzalez-Gaitan
Summary of the project:
Tsg101 protein has two-fold significance for human health: it represents an important anti-viral drug target and its deregulated expression is a hallmark of various cancer types. In fact, both pro- and anti-oncogenic activities of Tsg101 have been reported. At a cellular level, Tsg101 directs cargo sorting during endocytosis, is involved in cytokinesis and budding of HIV and other viruses. Novel data of the IIMCB applicant indicate that Tsg101 has an alternative function as a regulator of transcription in different cell signaling pathways. These data are the basis for the current proposal.
Due to the opposing roles of Tsg101 in specific transcriptional responses, we hypothesize that Tsg101 could act either as a tumor suppressor or a cancer-promoting protein depending on the tumor-specific aberration in signaling pathways. This would explain the controversy in the literature. Moreover, the role of Tsg101 in transcription has not been systematically investigated. Our project aims to fill this gap by a comprehensive combination of innovative experimental approaches.
We propose to study the novel transcriptional roles of Tsg101 in cultured cells, in model organisms as well as in normal and diseased human tissues, complemented by in silico analyses. To achieve its goals, the project involves a wide spectrum of complementary and innovative methodologies, ranging from molecular and cellular assays, global transcriptome analyses, functional studies in model organisms, to human cancer arrays. Complementing the Affymetrix microarrays, a key innovative technology to obtain unbiased and precise transcriptomic results will be the NanoString mRNA profiling.
The results of the project are expected to have three-fold significance. First, they should identify the molecular mechanisms and targets of Tsg101 action in transcription. This is expected to provide conceptual advances of fundamental knowledge about the relationship between endocytosis, transcription and cancer. Second, the project should identify any potential adverse effects of an available Tsg101 inhibitor on cellular transcription. This will be of applicable value for further development of anti-viral drugs with minimal side effects targeting Tsg101. Third, the knowledge of the detailed expression profile of Tsg101 and its transcriptional targets in various clinically characterized tumors could help to resolve controversy over the pro- or anti-oncogenic properties of Tsg101. This may contribute to diagnostic or prognostic applications in the clinical practice.
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Project supported by a grant from Switzerland through the Swiss Contribution to the enlarged European Union