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Regulation of nuclear gene expression by PK 11195, a ligand specific for the mitochondrial 18 kDa translocator protein (TSPO) (15, 30, and 45 minutes of exposure)

ABSTRACT: It is known that application of TSPO ligands as well as knockdown of the mitochondrial 18 kDa translocator protein (TSPO) modulate viability, proliferation, adhesion, and migration of glioblastoma cells, as well as angiogenesis. To study the ability of the TSPO to regulate gene expression in relation to these functions we applied microarray analysis of gene expression to U118MG glioblastoma cells. Seen at the time points of 15, 30, and 45 minutes, the 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 for modulation of general gene expression. These changes peaked at 30 minutes. Thus, it appears that the TSPO is part of the retrograde mitochondrial-nuclear signaling pathway for modulation of gene expression. Consequently, our data indicate that this is a major venue whereby TSPO may drive its numerous functional effects. 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 abstract of annual meetingof the israel society for neuroscience, section B, abstract # 98.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85697 | GEO | 2016/08/17

SECONDARY ACCESSION(S): PRJNA339121

REPOSITORIES: GEO

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Project description:We hypothesized that the potential ability of the 18 kDa mitochondrial translocator protein (TSPO) to regulate gene expression may underlie its numerous reported functions, ranging from mitochondrial activity till mental disorders. Therefore, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 1 hr the TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. After 24 hrs primarily gene expression for enzymes and other proteins is changed. The associated gene products are known to affect various cellular functions: programmed cell death, cell cycle, viability, proliferation, migration, differentiation, development, tumorigenesis, and inflammatory / immune responses. Our microscopic studies showed intense TSPO mitochondrial labeling but no TSPO signal in the cell nuclei. Thus, it appears that the TSPO is part of the retrograde mitochondrial-nuclear signaling pathway for modulation of gene expression and thereby may exert its numerous effects on cell function, phenotype, and disease. U118MG cells (1.255 Ã 106) were seeded in Petri dishes (i.e. 28.5 Ã 103 cells / cm2) and allowed to proliferate for 3 days in full medium. Experiments for gene expression assayed with microarray typically consisted of three experimental groups and a vehicle control group (n = 3 for each group). Serum deprived medium was applied for 24 hrs, in the experimental groups ending with the inclusion a choice of various PK 11195 exposures i.e. either 1 hr, 3 hrs, or 24 hrs. Exposure to PK 11195 implies serum deprived medium with 1% alcohol (vehicle) and PK 11195 (25 ÂµM final concentration) for the required time period. 25 ÂµM of PK 11195 is the optimal concentration for these types of experiments with U118MG cells (Kugler et al., 2008). The cells were collected by trypsinization, washed by centrifugation in phosphate buffered saline (PBS) (400 Ã g, 5 min), and lysed [RLT lysis buffer provided with the RNeasy Mini Kit diluted with Î²-mercaptoethanol (1 : 100)], according to the manufacturer's instructions. Lysates were stored at -70oC.

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Regulation of nuclear gene expression by PK 11195, a ligand specific for the mitochondrial 18 kDa translocator protein (TSPO) (15, 30, and 45 minutes of exposure)

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