Role of the CCAAT-Binding Protein NFY in SCA17 Pathogenesis
| Autor: | Hao-Chun Wang, Li-Ching Lee, Chiung-Mei Chen, Guey Jen Lee-Chen, Chung Hsin Wu, Jung-Yaw Lin, Guan Chiun Lee, Ming Tsan Su, Hsiao-Han Hsieh, Hsiu Mei Hsieh-Li, I-Sheng Chiu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
lcsh:Medicine
Gene Expression Pathogenesis Biology Biochemistry Microbiology Cytopathology Transcription (biology) Diagnostic Medicine Heat shock protein Pathology Humans Spinocerebellar Ataxias Heat shock lcsh:Science HSPA8 Protein Interactions Promoter Regions Genetic Transcription factor Endoplasmic Reticulum Chaperone BiP Neuropathology Heat-Shock Proteins Multidisciplinary Movement Disorders Binding protein lcsh:R HEK 293 cells Proteins Neurodegenerative Diseases Transfection TATA-Box Binding Protein Molecular biology Cerebellar Disorders Protein Transport HEK293 Cells Neurology CCAAT-Binding Factor Anatomical Pathology Medicine lcsh:Q Mutant Proteins Research Article Protein Binding |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 4, p e35302 (2012) |
| ISSN: | 1932-6203 |
| Popis: | Spinocerebellar ataxia 17 (SCA17) is caused by expansion of the polyglutamine (polyQ) tract in human TATA-box binding protein (TBP) that is ubiquitously expressed in both central nervous system and peripheral tissues. The spectrum of SCA17 clinical presentation is broad. The precise pathogenic mechanism in SCA17 remains unclear. Previously proteomics study using a cellular model of SCA17 has revealed reduced expression of heat shock 70 kDa protein 5 (HSPA5) and heat shock 70 kDa protein 8 (HSPA8), suggesting that impaired protein folding may contribute to the cell dysfunction of SCA17 (Lee et al., 2009). In lymphoblastoid cells, HSPA5 and HSPA8 expression levels in cells with mutant TBP were also significantly lower than that of the control cells (Chen et al., 2010). As nuclear transcription factor Y (NFY) has been reported to regulate HSPA5 transcription, we focused on if NFY activity and HSPA5 expression in SCA17 cells are altered. Here, we show that TBP interacts with NFY subunit A (NFYA) in HEK-293 cells and NFYA incorporated into mutant TBP aggregates. In both HEK-293 and SH-SY5Y cells expressing TBP/Q(61~79), the level of soluble NFYA was significantly reduced. In vitro binding assay revealed that the interaction between TBP and NFYA is direct. HSPA5 luciferase reporter assay and endogenous HSPA5 expression analysis in NFYA cDNA and siRNA transfection cells further clarified the important role of NFYA in regulating HSPA5 transcription. In SCA17 cells, HSPA5 promoter activity was activated as a compensatory response before aggregate formation. NFYA dysfunction was indicated in SCA17 cells as HSPA5 promoter activity reduced along with TBP aggregate formation. Because essential roles of HSPA5 in protection from neuronal apoptosis have been shown in a mouse model, NFYA could be a target of mutant TBP in SCA17. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|