Faehling, Michael and Persson, Anja Bondke and Klinger, Bertram and Benko, Edgar and Steege, Andreas and Kasim, Mumtaz and Patzak, Andreas and Persson, Pontus B. and Wolf, Gunter and Bluethgen, Nils and Mrowka, Ralf (2012) Multilevel regulation of HIF-1 signaling by TTP. MOLECULAR BIOLOGY OF THE CELL, 23 (20). pp. 4129-4141. ISSN 1059-1524, 1939-4586
Full text not available from this repository. (Request a copy)Abstract
Hypoxia-inducible factor-1 (HIF-1) is a well-studied transcription factor mediating cellular adaptation to hypoxia. It also plays a crucial role under normoxic conditions, such as in inflammation, where its regulation is less well understood. The 3'-untranslated region (UTR) of HIF-1 alpha mRNA is among the most conserved UTRs in the genome, hinting toward posttranscriptional regulation. To identify potential trans factors, we analyzed a large compilation of expression data. In contrast to its known function of being a negative regulator, we found that tristetraprolin (TTP) positively correlates with HIF-1 target genes. Mathematical modeling predicts that an additional level of posttranslational regulation of TTP can explain the observed positive correlation between TTP and HIF-1 signaling. Mechanistic studies revealed that TTP indeed changes its mode of regulation from destabilizing to stabilizing HIF-1 alpha mRNA upon phosphorylation by p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2. Using a model of monocyte-to-macrophage differentiation, we show that TTP-driven HIF-1 alpha mRNA stabilization is crucial for cell migration. This demonstrates the physiological importance of a hitherto-unknown mechanism for multilevel regulation of HIF-1 alpha in normoxia.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACTIVATED PROTEIN-KINASE; MESSENGER-RNA STABILITY; RICH ELEMENT; TRANSLATIONAL CONTROL; POSTTRANSCRIPTIONAL REGULATION; POSTTRANSLATIONAL REGULATION; TRISTETRAPROLIN EXPRESSION; MACROPHAGE DIFFERENTIATION; GENE-EXPRESSION; HYPOXIA; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 05 May 2020 05:57 |
| Last Modified: | 05 May 2020 05:57 |
| URI: | https://pred.uni-regensburg.de/id/eprint/17944 |
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