Abstract
The regulation of CCAAT/enhancer-binding protein-homologous protein (CHOP), an endoplasmic reticulum (ER) stress-response factor, is key to cellular survival. Hypoxia is a physiologically important stress that induces cell death in the context of the ER, especially in solid tumors. Although our previous studies have suggested that Cyclophilin B (CypB), a molecular chaperone, has a role in ER stress, currently, there is no direct information supporting its mechanism under hypoxia. Here, we demonstrate for the first time that CypB is associated with p300 E4 ligase, induces ubiquitination and regulates the proteasomal turnover of CHOP, one of the well-known pro-apoptotic molecules under hypoxia. Our findings show that CypB physically interacts with the N-terminal α-helix domain of CHOP under hypoxia and cooperates with p300 to modulate the ubiquitination of CHOP. We also show that CypB is transcriptionally induced through ATF6 under hypoxia. Collectively, these findings demonstrate that CypB prevents hypoxia-induced cell death through modulation of ubiquitin-mediated CHOP protein degradation, suggesting that CypB may have an important role in the tight regulation of CHOP under hypoxia.
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Abbreviations
- CypB:
-
cyclophilin B
- PPIase:
-
peptidyl-prolyl cis–trans isomerase
- ER:
-
endoplasmic reticulum
- GRP:
-
glucose-regulated protein
- UPR:
-
unfolded protein response
- IRE1α:
-
inositol-requiring transmembrane kinase and endonuclease 1α
- PERK:
-
RNA-dependent protein kinase-like ER kinase
- ATF6:
-
activating transcription factor 6
- ATF4:
-
activating transcription factor 4
- eIF2α:
-
eukaryotic translation initiation factor 2α
- CHOP:
-
CCAAT/enhancer-binding protein-homologous protein
- JNK:
-
c-Jun NH2-terminal kinase
- TUNEL:
-
terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling
- CHX:
-
cycloheximide
- BCCAO:
-
bilateral common carotid arteries occlusion
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Acknowledgements
This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health, Welfare, and Family Affairs, Republic of Korea (A092125) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (20120009380).
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Jeong, K., Kim, H., Kim, K. et al. Cyclophilin B is involved in p300-mediated degradation of CHOP in tumor cell adaptation to hypoxia. Cell Death Differ 21, 438–450 (2014). https://doi.org/10.1038/cdd.2013.164
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DOI: https://doi.org/10.1038/cdd.2013.164
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