Normoxic destabilization of ATF-4 depends on proteasomal degradation
| Autor: | Marieke Wottawa, D. M. Katschinski, Jens Köditz |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Transcriptional Activation
Proteasome Endopeptidase Complex Physiology Immunoprecipitation viruses genetic processes Procollagen-Proline Dioxygenase chemistry.chemical_element Activating Transcription Factor 4 Biology environment and public health Oxygen Cell Line 03 medical and health sciences Oxygen Consumption 0302 clinical medicine Cell Line Tumor Gene expression medicine Humans RNA Small Interfering 030304 developmental biology 0303 health sciences fungi Ubiquitination Hypoxia (medical) Molecular biology Cell biology Proteasome chemistry Cell culture 030220 oncology & carcinogenesis Limiting oxygen concentration medicine.symptom Transcription Factor CHOP HeLa Cells |
| Zdroj: | Acta Physiologica. 198:457-463 |
| ISSN: | 1748-1716 1748-1708 |
| Popis: | Aim: 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. Methods: 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. Results: 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. Conclusion: 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 degradation may play a critical role in linking cell fate decisions to oxygen availability. |
| Databáze: | OpenAIRE |
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