The E3 ubiquitin ligase thyroid hormone receptor-interacting protein 12 targets pancreas transcription factor 1a for proteasomal degradation
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc..
Pancreas transcription factor 1a (PTF1a) plays a crucial role in the early development of the pancreas and in the maintenance of the acinar cell phenotype. Several transcriptional mechanisms regulating expression of PTF1a have been identified. However, regulation of PTF1a protein stability and degradation is still unexplored. Here, we report that inhibition of proteasome leads to elevated levels of PTF1a and to the existence of polyubiquitinated forms of PTF1a. We used the Sos recruitment system, an alternative two-hybrid system method to detect protein-protein interactions in the cytoplasm and to map the interactome of PTF1a. We identified TRIP12 (thyroid hormone receptor-interacting protein 12), an E3 ubiquitin-protein ligase as a new partner of PTF1a. We confirmed PTF1a/TRIP12 interaction in acinar cell lines and in co-transfected HEK-293T cells. The protein stability of PTF1a is significantly increased upon decreased expression of TRIP12. It is reduced upon overexpression of TRIP12 but not a catalytically inactive TRIP12-C1959A mutant. We identified a region of TRIP12 required for interaction and identified lysine 312 of PTF1a as essential for proteasomal degradation. We also demonstrate that TRIP12 down-regulates PTF1a transcriptional and antiproliferative activities. Our data suggest that an increase in TRIP12 expression can play a part in PTF1a down-regulation and indicate that PTF1a/TRIP12 functional interaction may regulate pancreatic epithelial cell homeostasis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2014 |
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| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:289 |
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| Enthalten in: |
The Journal of biological chemistry - 289(2014), 51 vom: 19. Dez., Seite 35593-604 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hanoun, Naïma [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.04.2015 Date Revised 05.02.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1074/jbc.M114.620104 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM243154135 |
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| 100 | 1 | |a Hanoun, Naïma |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The E3 ubiquitin ligase thyroid hormone receptor-interacting protein 12 targets pancreas transcription factor 1a for proteasomal degradation |
| 264 | 1 | |c 2014 | |
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| 500 | |a Date Revised 05.02.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. | ||
| 520 | |a Pancreas transcription factor 1a (PTF1a) plays a crucial role in the early development of the pancreas and in the maintenance of the acinar cell phenotype. Several transcriptional mechanisms regulating expression of PTF1a have been identified. However, regulation of PTF1a protein stability and degradation is still unexplored. Here, we report that inhibition of proteasome leads to elevated levels of PTF1a and to the existence of polyubiquitinated forms of PTF1a. We used the Sos recruitment system, an alternative two-hybrid system method to detect protein-protein interactions in the cytoplasm and to map the interactome of PTF1a. We identified TRIP12 (thyroid hormone receptor-interacting protein 12), an E3 ubiquitin-protein ligase as a new partner of PTF1a. We confirmed PTF1a/TRIP12 interaction in acinar cell lines and in co-transfected HEK-293T cells. The protein stability of PTF1a is significantly increased upon decreased expression of TRIP12. It is reduced upon overexpression of TRIP12 but not a catalytically inactive TRIP12-C1959A mutant. We identified a region of TRIP12 required for interaction and identified lysine 312 of PTF1a as essential for proteasomal degradation. We also demonstrate that TRIP12 down-regulates PTF1a transcriptional and antiproliferative activities. Our data suggest that an increase in TRIP12 expression can play a part in PTF1a down-regulation and indicate that PTF1a/TRIP12 functional interaction may regulate pancreatic epithelial cell homeostasis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Basic Helix-Loop-Helix Transcription Factor (bHLH) | |
| 650 | 4 | |a E3 Ubiquitin Ligase | |
| 650 | 4 | |a Pancreas | |
| 650 | 4 | |a Pancreatic Cancer | |
| 650 | 4 | |a Proteasome | |
| 650 | 4 | |a Protein Degradation | |
| 650 | 4 | |a Protein-Protein Interaction | |
| 650 | 4 | |a Transcription Factor | |
| 650 | 4 | |a Ubiquitylation (Ubiquitination) | |
| 650 | 4 | |a Yeast Two-Hybrid | |
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| 650 | 7 | |a transcription factor PTF1 |2 NLM | |
| 650 | 7 | |a TRIP12 protein, human |2 NLM | |
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| 650 | 7 | |a Ubiquitin-Protein Ligases |2 NLM | |
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| 650 | 7 | |a Proteasome Endopeptidase Complex |2 NLM | |
| 650 | 7 | |a EC 3.4.25.1 |2 NLM | |
| 700 | 1 | |a Fritsch, Samuel |e verfasserin |4 aut | |
| 700 | 1 | |a Gayet, Odile |e verfasserin |4 aut | |
| 700 | 1 | |a Gigoux, Véronique |e verfasserin |4 aut | |
| 700 | 1 | |a Cordelier, Pierre |e verfasserin |4 aut | |
| 700 | 1 | |a Dusetti, Nelson |e verfasserin |4 aut | |
| 700 | 1 | |a Torrisani, Jérôme |e verfasserin |4 aut | |
| 700 | 1 | |a Dufresne, Marlène |e verfasserin |4 aut | |
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