Oxygen-regulated expression of the RNA-binding proteins RBM3 and CIRP by a HIF-1-independent mechanism

The transcriptional regulation of several dozen genes in response to low oxygen tension is mediated by hypoxia-inducible factor 1 (HIF-1), a heterodimeric protein composed of two subunits, HIF-1alpha and HIF-1beta. In the HIF-1alpha-deficient human leukemic cell line, Z-33, exposed to mild (8% O(2))...

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Vydáno v:	Journal of cell science Ročník 117; číslo Pt 9; s. 1785
Hlavní autoři:	Wellmann, Sven, Bührer, Christoph, Moderegger, Eva, Zelmer, Andrea, Kirschner, Renate, Koehne, Petra, Fujita, Jun, Seeger, Karl
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England 01.04.2004
Témata:	Animals Antioxidants - pharmacology Aryl Hydrocarbon Receptor Nuclear Translocator Burkitt Lymphoma - genetics Burkitt Lymphoma - metabolism Carcinoma, Hepatocellular - genetics Cell Hypoxia - drug effects Cell Hypoxia - genetics Cell Hypoxia - physiology Cell Line, Tumor Cyanides - pharmacology Dactinomycin - pharmacology DNA-Binding Proteins - deficiency DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Gene Expression Profiling Gene Expression Regulation - drug effects Humans Hypothermia - genetics Hypoxia-Inducible Factor 1, alpha Subunit Mice Mitochondria - drug effects Mitochondria - metabolism Oxidation-Reduction - drug effects Oxygen - pharmacology Receptors, Aryl Hydrocarbon - deficiency Receptors, Aryl Hydrocarbon - genetics Receptors, Aryl Hydrocarbon - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism RNA-Binding Proteins - genetics Sodium Azide - pharmacology Transcription Factors - deficiency Transcription Factors - genetics Transcription Factors - metabolism Transcriptional Activation - drug effects
ISSN:	0021-9533
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Shrnutí:	The transcriptional regulation of several dozen genes in response to low oxygen tension is mediated by hypoxia-inducible factor 1 (HIF-1), a heterodimeric protein composed of two subunits, HIF-1alpha and HIF-1beta. In the HIF-1alpha-deficient human leukemic cell line, Z-33, exposed to mild (8% O(2)) or severe (1% O(2)) hypoxia, we found significant upregulation of two related heterogenous nuclear ribonucleoproteins, RNA-binding motif protein 3 (RBM3) and cold inducible RNA-binding protein (CIRP), which are highly conserved cold stress proteins with RNA-binding properties. Hypoxia also induced upregulation of RBM3 and CIRP in the murine HIF-1beta-deficient cell line, Hepa-1 c4. In various HIF-1 competent cells, RBM3 and CIRP were induced by moderate hypothermia (32 degrees C) but hypothermia was ineffective in increasing HIF-1alpha or vascular endothelial growth factor (VEGF), a known HIF-1 target. In contrast, iron chelators induced VEGF but not RBM3 or CIRP. The RBM3 and CIRP mRNA increase after hypoxia was inhibited by actinomycin-D, and in vitro nuclear run-on assays demonstrated specific increases in RBM3 and CIRP mRNA after hypoxia, which suggests that regulation takes place at the level of gene transcription. Hypoxia-induced RBM3 or CIRP transcription was inhibited by the respiratory chain inhibitors NaN(3) and cyanide in a dose-dependent fashion. However, cells depleted of mitochondria were still able to upregulate RBM3 and CIRP in response to hypoxia. Thus, RBM3 and CIRP are adaptatively expressed in response to hypoxia by a mechanism that involves neither HIF-1 nor mitochondria.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9533
DOI:	10.1242/jcs.01026