Post-translational regulation of the tumour suppressor IRF-1
IRF-1 (Interferon Regulatory Factor 1) is a transcription factor first identified as a regulator of Interferon expression. Two decades after its discovery, IRF-1 has been shown to be involved in numerous other pathways including apoptosis, cell cycle regulation, DNA damage/repair, immune cell develo...
| Main Author: | |
|---|---|
| Format: | Thesis (University of Nottingham only) |
| Language: | English |
| Published: |
2010
|
| Online Access: | https://eprints.nottingham.ac.uk/13893/ |
| _version_ | 1848791829923758080 |
|---|---|
| author | Garvin, Alexander |
| author_facet | Garvin, Alexander |
| author_sort | Garvin, Alexander |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | IRF-1 (Interferon Regulatory Factor 1) is a transcription factor first identified as a regulator of Interferon expression. Two decades after its discovery, IRF-1 has been shown to be involved in numerous other pathways including apoptosis, cell cycle regulation, DNA damage/repair, immune cell development and inflammation. Transcriptional regulation of IRF-1 by a number of external agents has been extensively studied, however almost nothing is known about the posttranslational regulation of IRF-1 activity. In this study IRF-1 is shown to be phosphorylated at Thr180 by GSK3β (Glycogen Synthase Kinase 3β). Phosphorylated Thr180 promotes interaction with the ubiquitin E3 ligase SCFFbxw7u, (Skp1-Cu11-Fbxw7α) which increases turnover of IRF-1 protein. Phosphorylation dependent ubiquitination of IRF-1 was confirmed, as substitution of Thr180 to alanine reduced IRF-1 ubiquitination and increased stability. Enhanced phosphorylation of IRF-1 (by increasing GSK3β expression) promotes increased ubiquitination/degradation. Transactivation of the TRAIL (TNFα Related Apoptosis Inducing Ligand) promoter by IRF-1 was found to be dependent on GSK3β phosphorylation of Thr180 by use of reporter assays and inducible expression of IRF-1 in breast cancer cell lines. Importantly IRF-1 activity on the TRAIL promoter is dependent on proper turnover by the UPS (Ubiquitin Proteasome System), as chemical inhibition of the proteasome, or reduction in IRF-1 ubiquitination reduced activity in reporter assays. This suggests that phosphorylation of IRF-1 by GSK3β acts as a destruction signal through association with SCFFbxw7a. This signal dependent turnover of IRF-1 is required for proper transcriptional activation of the TRAIL promoter. |
| first_indexed | 2025-11-14T18:34:44Z |
| format | Thesis (University of Nottingham only) |
| id | nottingham-13893 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T18:34:44Z |
| publishDate | 2010 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-138932025-02-28T11:27:35Z https://eprints.nottingham.ac.uk/13893/ Post-translational regulation of the tumour suppressor IRF-1 Garvin, Alexander IRF-1 (Interferon Regulatory Factor 1) is a transcription factor first identified as a regulator of Interferon expression. Two decades after its discovery, IRF-1 has been shown to be involved in numerous other pathways including apoptosis, cell cycle regulation, DNA damage/repair, immune cell development and inflammation. Transcriptional regulation of IRF-1 by a number of external agents has been extensively studied, however almost nothing is known about the posttranslational regulation of IRF-1 activity. In this study IRF-1 is shown to be phosphorylated at Thr180 by GSK3β (Glycogen Synthase Kinase 3β). Phosphorylated Thr180 promotes interaction with the ubiquitin E3 ligase SCFFbxw7u, (Skp1-Cu11-Fbxw7α) which increases turnover of IRF-1 protein. Phosphorylation dependent ubiquitination of IRF-1 was confirmed, as substitution of Thr180 to alanine reduced IRF-1 ubiquitination and increased stability. Enhanced phosphorylation of IRF-1 (by increasing GSK3β expression) promotes increased ubiquitination/degradation. Transactivation of the TRAIL (TNFα Related Apoptosis Inducing Ligand) promoter by IRF-1 was found to be dependent on GSK3β phosphorylation of Thr180 by use of reporter assays and inducible expression of IRF-1 in breast cancer cell lines. Importantly IRF-1 activity on the TRAIL promoter is dependent on proper turnover by the UPS (Ubiquitin Proteasome System), as chemical inhibition of the proteasome, or reduction in IRF-1 ubiquitination reduced activity in reporter assays. This suggests that phosphorylation of IRF-1 by GSK3β acts as a destruction signal through association with SCFFbxw7a. This signal dependent turnover of IRF-1 is required for proper transcriptional activation of the TRAIL promoter. 2010-07-20 Thesis (University of Nottingham only) NonPeerReviewed application/pdf en arr https://eprints.nottingham.ac.uk/13893/1/523080.pdf Garvin, Alexander (2010) Post-translational regulation of the tumour suppressor IRF-1. PhD thesis, University of Nottingham. |
| spellingShingle | Garvin, Alexander Post-translational regulation of the tumour suppressor IRF-1 |
| title | Post-translational regulation of the tumour suppressor IRF-1 |
| title_full | Post-translational regulation of the tumour suppressor IRF-1 |
| title_fullStr | Post-translational regulation of the tumour suppressor IRF-1 |
| title_full_unstemmed | Post-translational regulation of the tumour suppressor IRF-1 |
| title_short | Post-translational regulation of the tumour suppressor IRF-1 |
| title_sort | post-translational regulation of the tumour suppressor irf-1 |
| url | https://eprints.nottingham.ac.uk/13893/ |