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Int. J. Mol. Sci. 2017, 18(4), 786; doi:10.3390/ijms18040786

Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling

1
The Ruth and Bruce Rappaport Faculty of Medicine, Department of Neuroscience, Technion—Israel Institute of Technology, Haifa 32525433, Israel
2
Faculty of Chemistry, Department of Organic Chemistry, Technion—Israel Institute of Technology, Haifa 3200003, Israel
3
Schaller Research Group at the University of Heidelberg and the German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg 69120, Germany
These authors contributed equally to this work.
New Address: Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Julian Claveria, 33008 Oviedo (Asturias), Spain.
*
Authors to whom correspondence should be addressed.
Academic Editors: Giovanni Natile and Nunzio Denora
Received: 19 February 2017 / Revised: 24 March 2017 / Accepted: 27 March 2017 / Published: 7 April 2017
(This article belongs to the Special Issue Translocator Protein (TSPO))
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Abstract

It is known that knockdown of the mitochondrial 18 kDa translocator protein (TSPO) as well as TSPO ligands modulate various functions, including functions related to cancer. To study the ability of TSPO to regulate gene expression regarding such functions, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 15 min, the classical TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. These changes also included gene products that are part of the canonical pathway serving to modulate general gene expression. These changes are in accord with real-time, reverse transcriptase (RT) PCR. At the time points of 15, 30, 45, and 60 min, as well as 3 and 24 h of PK 11195 exposure, the functions associated with the changes in gene expression in these glioblastoma cells covered well known TSPO functions. These functions included cell viability, proliferation, differentiation, adhesion, migration, tumorigenesis, and angiogenesis. This was corroborated microscopically for cell migration, cell accumulation, adhesion, and neuronal differentiation. Changes in gene expression at 24 h of PK 11195 exposure were related to downregulation of tumorigenesis and upregulation of programmed cell death. In the vehicle treated as well as PK 11195 exposed cell cultures, our triple labeling showed intense TSPO labeling in the mitochondria but no TSPO signal in the cell nuclei. Thus, mitochondrial TSPO appears to be part of the mitochondria-to-nucleus signaling pathway for modulation of nuclear gene expression. The novel TSPO ligand 2-Cl-MGV-1 appeared to be very specific regarding modulation of gene expression of immediate early genes and transcription factors. View Full-Text
Keywords: modulation of nuclear gene expression; mitochondrial 18 kDa translocator protein (TSPO); TSPO ligand; PK 11195; 2-Cl-MGV-1; retrograde mitochondrial-nuclear signaling pathway; microscopy; mitochondria; cell nucleus modulation of nuclear gene expression; mitochondrial 18 kDa translocator protein (TSPO); TSPO ligand; PK 11195; 2-Cl-MGV-1; retrograde mitochondrial-nuclear signaling pathway; microscopy; mitochondria; cell nucleus
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Yasin, N.; Veenman, L.; Singh, S.; Azrad, M.; Bode, J.; Vainshtein, A.; Caballero, B.; Marek, I.; Gavish, M. Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling. Int. J. Mol. Sci. 2017, 18, 786.

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