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  4. IFN-g-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD
 
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2018
Journal Article
Titel

IFN-g-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD

Abstract
Interferon-gamma (IFN-g) is a pleiotropic cytokine that exerts important functions in inflammation, infectious diseases, and cancer. The large GTPase human guanylate-binding protein 1 (GBP-1) is among the most strongly IFN-g-induced cellular proteins. Previously, it has been shown that GBP-1 mediates manifold cellular responses to IFN-g including the inhibition of proliferation, spreading, migration, and invasion and through this exerts anti-tumorigenic activity. However, the mechanisms of GBP-1 anti-tumorigenic activities remain poorly understood. Here, we elucidated the molecular mechanism of the human GBP-1-mediated suppression of proliferation by demonstrating for the first time a cross-talk between the anti-tumorigenic IFN-g and Hippo pathways. The a9-helix of GBP-1 was found to be sufficient to inhibit proliferation. Protein-binding and molecular modeling studies revealed that the a9-helix binds to the DNA-binding domain of the Hippo signaling transcription factor TEA domain protein (TEAD) mediated by the 376VDHLFQK382 sequence at the N-terminus of the GBP-1-a9-helix. Mutation of this sequence resulted in abrogation of both TEAD interaction and suppression of proliferation. Further on, the interaction caused inhibition of TEAD transcriptional activity associated with the down-regulation of TEAD-target genes. In agreement with these results, IFN-g treatment of the cells also impaired TEAD activity, and this effect was abrogated by siRNA-mediated inhibition of GBP-1 expression. Altogether, this demonstrated that the a9-helix is the proliferation inhibitory domain of GBP-1, which acts independent of the GTPase activity through the inhibition of the Hippo transcription factor TEAD in mediating the anti-proliferative cell response to IFN-g.
Author(s)
Unterer, B.
Wiesmann, V.
Gunasekaran, M.
Sticht, H.
Tenkerian, C.
Behrens, J.
Leone, M.
Engel, F.B.
Britzen-Laurent, N.
Naschberger, E.
Wittenberg, T.
Stürzl, M.
Zeitschrift
Biochemical Journal
Thumbnail Image
DOI
10.1042/BCJ20180123
Language
English
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