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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Mol+Cell+Biol 2008 ; 28 (1): 93-107 Nephropedia Template TP
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RNA-binding proteins HuR and PTB promote the translation of hypoxia-inducible factor 1alpha #MMPMID17967866
Galban S; Kuwano Y; Pullmann R Jr; Martindale JL; Kim HH; Lal A; Abdelmohsen K; Yang X; Dang Y; Liu JO; Lewis SM; Holcik M; Gorospe M
Mol Cell Biol 2008[Jan]; 28 (1): 93-107 PMID17967866show ga
The levels of hypoxia-inducible factor 1alpha (HIF-1alpha) are tightly controlled. Here, we investigated the posttranscriptional regulation of HIF-1alpha expression in human cervical carcinoma HeLa cells responding to the hypoxia mimetic CoCl(2). Undetectable in untreated cells, HIF-1alpha levels increased dramatically in CoCl(2)-treated cells, while HIF-1alpha mRNA levels were unchanged. HIF-1alpha translation was potently elevated by CoCl(2) treatment, as determined by de novo translation analysis and by monitoring the polysomal association of HIF-1alpha mRNA. An internal ribosome entry site in the HIF-1alpha 5' untranslated region (UTR) was found to enhance translation constitutively, but it did not further induce translation in response to CoCl(2) treatment. Instead, we postulated that RNA-binding proteins HuR and PTB, previously shown to bind HIF-1alpha mRNA, participated in its translational upregulation after CoCl(2) treatment. Indeed, both RNA-binding proteins were found to bind HIF-1alpha mRNA in a CoCl(2)-inducible manner as assessed by immunoprecipitation of endogenous ribonucleoprotein complexes. Using a chimeric reporter, polypyrimidine tract-binding protein (PTB) was found to bind the HIF-1alpha 3'UTR, while HuR associated principally with the 5'UTR. Lowering PTB expression or HuR expression using RNA interference reduced HIF-1alpha translation and expression levels but not HIF-1alpha mRNA abundance. Conversely, HIF-1alpha expression and translation in response to CoCl(2) were markedly elevated after HuR overexpression. We propose that HuR and PTB jointly upregulate HIF-1alpha translation in response to CoCl(2).