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

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autorinnen und Autoren: Unterer B, Wiesmann V, Gunasekaran M, Sticht H, Tenkerian C, Behrens J, Leone M, Engel F, Britzen-Laurent N, Naschberger E, Wittenberg T, Stürzl M
Zeitschrift: Biochemical Journal
Jahr der Veröffentlichung: 2018
Band: 475
Heftnummer: 18
Seitenbereich: 2955-2967
ISSN: 0264-6021
eISSN: 1470-8728


Abstract

Interferon-gamma (IFN-γ) 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-γ-induced cellular proteins. Previously, it has been shown that GBP-1 mediates manifold cellular responses to IFN-γ 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-γ and Hippo pathways. The α9-helix of GBP-1 was found to be sufficient to inhibit proliferation. Protein-binding and molecular modeling studies revealed that the α9-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-α9-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-γ 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 α9-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-γ.


FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Behrens, Jürgen Prof. Dr.
Lehrstuhl für Experimentelle Medizin II (Molekulare Tumorforschung)
Engel, Felix Prof. Dr. rer. nat.
Nephropathologische Abteilung im Pathologischen Institut
Gunasekaran, Mekala
Lehrstuhl für Experimentelle Medizin II (Molekulare Tumorforschung)
Naschberger, Elisabeth PD Dr.
Medizinische Fakultät
Sticht, Heinrich Prof. Dr.
Professur für Bioinformatik
Stürzl, Michael Prof. Dr.
Professur für Molekulare und Experimentelle Chirurgie
Unterer, Bea
Lehrstuhl für Biochemie und Molekulare Medizin
Wittenberg, Thomas PD Dr.
Technische Fakultät


Einrichtungen weiterer Autorinnen und Autoren

Fraunhofer-Institut für Integrierte Schaltungen (IIS)


Zitierweisen

APA:
Unterer, B., Wiesmann, V., Gunasekaran, M., Sticht, H., Tenkerian, C., Behrens, J.,... Stürzl, M. (2018). IFN-γ-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD. Biochemical Journal, 475(18), 2955-2967. https://dx.doi.org/10.1042/BCJ20180123

MLA:
Unterer, Bea, et al. "IFN-γ-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD." Biochemical Journal 475.18 (2018): 2955-2967.

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Zuletzt aktualisiert 2019-30-07 um 07:17