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Repression of exogenous gene expression by the retinoic acid target gene G0S2
- Source :
- International Journal of Oncology
- Publication Year :
- 2013
- Publisher :
- Spandidos Publications, 2013.
-
Abstract
- The G0/G1 switch gene 2 (G0S2) is rapidly induced by all-trans-retinoic acid (RA)-treatment of acute promyelocytic leukemia (APL) and other cells. G0S2 regulates lipolysis via inhibition of adipose triglyceride lipase (ATGL). This study found that retinoic acid receptor (RAR), but not retinoid X receptor (RXR) agonists induced G0S2 expression in APL cells. Novel G0S2 functions were uncovered that included repression of exogenous gene expression and transcriptional activity. Transient G0S2 transfection repressed the activities of multiple reporter constructs (including the retinoid-regulated species RARĪ², UBE1L and G0S2); this occurred in diverse cell contexts. This inhibition was antagonized by siRNA-mediated G0S2 knockdown. To determine the inhibitory effects were not due to transient G0S2 expression, G0S2 was stably overex-pressed in cells without appreciable basal G0S2 expression. As expected, this repressed transcriptional activities. Intriguingly, transfection of G0S2 did not affect endogenous RARĪ², UBE1L or G0S2 expression. Hence, only exogenously expressed genes were affected by G0S2. The domain responsible for this repression was localized to the G0S2 hydrophobic domain (HD). This was the same region responsible for the ability of G0S2 to inhibit ATGL activity. Whether an interaction with ATGL accounted for this new G0S2 activity was studied. Mimicking the inhibition of ATGL by oleic acid treatment that increased lipid droplet size or ATGL siRNA knockdown did not recapitulate G0S2 repressive effects. Engineered gain of ATGL expression did not rescue G0S2 transcriptional repression either. Thus, transcriptional repression by G0S2 did not depend on the ability of G0S2 to inhibit ATGL. Subcellular localization studies revealed that endogenous and exogenously-expressed G0S2 proteins were localized to the cytoplasm, particularly in the perinuclear region. Expression of a mutant G0S2 species that lacked the HD domain altered cytosolic G0S2 localization. This linked G0S2 subcellular localization to G0S2 transcriptional repression. The potential mechanisms responsible for this G0S2 repression are examined.
- Subjects :
- G0/G1 switch gene 2
Cancer Research
Receptors, Retinoic Acid
Retinoic acid
Cell Cycle Proteins
Tretinoin
Ubiquitin-Activating Enzymes
Biology
Retinoid X receptor
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Leukemia, Promyelocytic, Acute
Cell Line, Tumor
transcriptional repression
Gene expression
retinoic acid
medicine
Humans
RNA, Small Interfering
Psychological repression
030304 developmental biology
0303 health sciences
Gene knockdown
Articles
Lipase
Transfection
Molecular biology
Gene Expression Regulation, Neoplastic
Retinoic acid receptor
Oncology
chemistry
030220 oncology & carcinogenesis
medicine.drug
Subjects
Details
- ISSN :
- 17912423 and 10196439
- Volume :
- 42
- Database :
- OpenAIRE
- Journal :
- International Journal of Oncology
- Accession number :
- edsair.doi.dedup.....1d53a202c7ac49645907a9fd49eb32f4