Normoxic destabilization of ATF-4 depends on proteasomal degradation

Acta Physiologica
Marieke WottawaDörthe M Katschinski

Abstract

Hypoxia-inducible gene expression is an important physiological adaptive mechanism in response to a decreased oxygen supply. We have recently described an oxygen- and prolyl-4-hydroxylase (PHD)3-dependent stabilization of the activating transcription factor 4 (ATF-4). The aim of the present study was to examine if the normoxic destabilization of ATF-4 is regulated by oxygen-dependent proteasomal degradation. We determined poly-ubiquitination of ATF-4 in normoxia compared to hypoxia by immunoprecipitation and immunoblots. Furthermore, we analysed the expression of the ATF-4 target gene GADD153 as a function of oxygen concentration. ATF-4 protein levels were not detectable in normoxia. Normoxic degradation correlated with an oxygen-dependent poly-ubiquitination of ATF-4, which was hindered by hypoxic incubation of the cells. As a result of hypoxia, GADD153 was expressed. The hypoxic GADD153 expression was attenuated or increased by transfecting the cells with ATF-4 siRNA or PHD3 siRNA respectively. Our results demonstrate the involvement of oxygen-dependent proteasomal degradation of ATF-4 in the hypoxia-induced expression of GADD153. Taken together, hypoxia/PHD3-regulated stabilization of ATF-4 by hindering oxygen-dependent degr...Continue Reading

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Citations

Apr 24, 2012·Acta Physiologica·M Fähling, P B Persson
Nov 1, 2011·Biochimica Et Biophysica Acta·Sarah Frankland-Searby, Sukesh R Bhaumik
Sep 29, 2011·Experimental Cell Research·Yusuke HiwatashiKen-ichi Yasumoto
Mar 16, 2013·Acta Physiologica·J Myllyharju
Sep 15, 2012·Biochimica Et Biophysica Acta·Camilla T AmbiveroAntonis S Zervos
Jul 31, 2016·Experimental Physiology·Eoin P Cummins, Ciara E Keogh
Jan 12, 2016·PLoS Biology·Carsten C ScholzCormac T Taylor
Feb 16, 2021·Frontiers in Pharmacology·Andrey A PoloznikovIrina G Gazaryan

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