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Mol Biol Cell. 2012 Oct;23(20):4129-41. doi: 10.1091/mbc.E11-11-0949. Epub 2012 Aug 23.

Multilevel regulation of HIF-1 signaling by TTP.

Author information

1
Institut für Vegetative Physiologie, Charité-Universitätsmedizin Berlin, D-10115 Berlin, Germany. michael.faehling@charite.de

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-1α 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-1α 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-1α mRNA stabilization is crucial for cell migration. This demonstrates the physiological importance of a hitherto-unknown mechanism for multilevel regulation of HIF-1α in normoxia.

PMID:
22918951
PMCID:
PMC3469526
DOI:
10.1091/mbc.E11-11-0949
[Indexed for MEDLINE]
Free PMC Article

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