EAF2 Suppresses Hypoxia-Induced Factor 1α Transcriptional Activity by Disrupting Its Interaction with Coactivator CBP/p300
| Autor: | Zhichao Mei, Wuhan Xiao, Xing Liu, Zhu Chen, Zhou Wang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Transcriptional Activation
Programmed cell death Hypoxia-Inducible Factor 1 Transcription Genetic Biology Cell Line Cell Line Tumor Coactivator medicine Humans p300-CBP Transcription Factors Hypoxia Promoter Regions Genetic Molecular Biology Cell Death Sirtuin 1 HEK 293 cells Cell Biology Articles Hep G2 Cells Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit Molecular biology Cell biology HIF1A Glucose HEK293 Cells biology.protein Signal transduction medicine.symptom Signal Transduction Transcription Factors |
| Popis: | Previous studies revealed that the potential tumor suppressor EAF2 binds to and stabilizes pVHL, suggesting that EAF2 may function by disturbing the hypoxia signaling pathway. However, the extent to which EAF2 affects hypoxia and the mechanisms underlying this activity remain largely unknown. In this study, we found that EAF2 is a hypoxia response gene harboring the hypoxia response element (HRE) in its promoter. By taking advantage of the pVHL-null cell lines RCC4 and 786-O, we demonstrated that hypoxia-induced factor 1 alpha (HIF-1 alpha), but not HIF-2 alpha, induced EAF2 under hypoxia. Subsequent experiments showed that EAF2 bound to and suppressed HIF-1 alpha but not HIF-2 alpha transactivity. In addition, we observed that EAF2 inhibition of HIF-1 activity resulted from the disruption of p300 recruitment and that this occurred independently of FIH-1 (factor inhibiting HIF-1) and Sirt1. Furthermore, we found that EAF2 protected cells against hypoxia-induced cell death and inhibited cellular uptake of glucose under hypoxic conditions, suggesting that EAF2 indeed may act by modulating the hypoxia-signaling pathway. Our findings not only uncover a unique feedback regulation loop between EAF2 and HIF-1 alpha but also provide a novel insight into the mechanism of EAF2 tumor suppression. |
| Databáze: | OpenAIRE |
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