PMID- 37738929
OWN - NLM
STAT- MEDLINE
DCOM- 20231108
LR  - 20231108
IS  - 1878-3252 (Electronic)
IS  - 0946-672X (Linking)
VI  - 80
DP  - 2023 Dec
TI  - ABCE1 selectively promotes HIF-1alpha transactivation of angiogenic gene expression.
PG  - 127307
LID - S0946-672X(23)00183-9 [pii]
LID - 10.1016/j.jtemb.2023.127307 [doi]
AB  - BACKGROUND: Copper (Cu), by inhibiting the factor inhibiting HIF-1 (FIH-1), 
      promotes the transcriptional activity of hypoxia-inducible factor-1 (HIF-1). 
      OBJECTIVE: The present study was undertaken to understand the molecular mechanism 
      by which Cu inhibits FIH-1. METHODS: Human umbilical vein endothelial cells 
      (HUVECs) were treated with dimethyloxalylglycine (DMOG) resulting in HIF-1alpha 
      accumulation and the FIH-1 protein complexes were pulled down for candidate 
      protein analysis. The metal binding sites were predicted by both MetalDetector 
      V2.0 and Metal Ion-Binding Site Prediction Server, and then the actual ability to 
      bind to Cu in vitro was tested by both Copper-Immobilized metal affinity 
      chromatography (Cu-IMAC) and Isothermal Titration Calorimetry (ITC). 
      Subsequently, subcellular localization was monitored by immunocytochemistry, 
      GFP-fusion protein expression plasmid and Western blotting in the nuclear 
      extract. The interaction of candidate protein with HIF-1alpha and FIH-1 was validated 
      by Co-Immunoprecipitation (Co-IP). Finally, the effect of candidate protein on 
      the FIH-1 structure and HIF-1alpha transcriptional activity was analyzed by the 
      InterEvDock3 web server and real-time quantitative RT-PCR. RESULTS: ATP-binding 
      cassette E1 (ABCE1) was present in the FIH-1 complexes and identified as a 
      leading Cu-binding protein as indicated by a number of possible Cu binding sites. 
      The ability of ABCE1 to bind Cu was demonstrated in vitro. ABCE1 entered the 
      nucleus along with FIH-1 under hypoxic conditions. Protein interaction analysis 
      revealed that ABCE1 prevented FIH-1 to bind iron ions, inhibiting FIH-1 enzymatic 
      activity. ABCE1 silencing suppressed the expression of Cu-dependent HIF-1 target 
      gene BNIP3, not that of Cu-independent IGF-2. CONCLUSION: The results demonstrate 
      that ABCE1, as a Cu-binding protein, enters the nucleus under hypoxic conditions 
      and inhibits FIH-1degradation of HIF-1alpha, thus promoting HIF-1 transactivation of 
      angiogenic gene expression.
CI  - Copyright (c) 2023 Elsevier GmbH. All rights reserved.
FAU - Sun, Lihui
AU  - Sun L
AD  - Regenerative Medicine Research Center, West China Hospital, Sichuan University, 
      Chengdu, Sichuan, China.
FAU - Ding, Xueqin
AU  - Ding X
AD  - Regenerative Medicine Research Center, West China Hospital, Sichuan University, 
      Chengdu, Sichuan, China; Analytical and Testing Center, Sichuan University, 
      Chengdu, Sichuan, China.
FAU - Kang, Y James
AU  - Kang YJ
AD  - Regenerative Medicine Research Center, West China Hospital, Sichuan University, 
      Chengdu, Sichuan, China. Electronic address: ykang7@uthsc.edu.
LA  - eng
PT  - Journal Article
DEP - 20230918
PL  - Germany
TA  - J Trace Elem Med Biol
JT  - Journal of trace elements in medicine and biology : organ of the Society for 
      Minerals and Trace Elements (GMS)
JID - 9508274
RN  - 0 (ABCE1 protein, human)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Carrier Proteins)
RN  - 789U1901C5 (Copper)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - 0 (Repressor Proteins)
RN  - 0 (HIF1A protein, human)
SB  - IM
MH  - Humans
MH  - ATP-Binding Cassette Transporters/genetics/metabolism
MH  - Carrier Proteins/metabolism
MH  - *Copper/pharmacology/metabolism
MH  - Endothelial Cells/metabolism
MH  - Gene Expression
MH  - Hypoxia
MH  - Mixed Function Oxygenases/genetics/metabolism
MH  - *Repressor Proteins/genetics/metabolism
MH  - Transcriptional Activation
OTO - NOTNLM
OT  - ABCE1
OT  - Copper-binding protein
OT  - FIH-1
OT  - HIF-1alpha transcriptional activity
COIS- Declaration of Competing Interest The authors declare that they have no conflicts 
      of interest with the contents of this article.
EDAT- 2023/09/23 11:42
MHDA- 2023/11/03 06:43
CRDT- 2023/09/22 18:11
PHST- 2023/06/27 00:00 [received]
PHST- 2023/09/10 00:00 [revised]
PHST- 2023/09/15 00:00 [accepted]
PHST- 2023/11/03 06:43 [medline]
PHST- 2023/09/23 11:42 [pubmed]
PHST- 2023/09/22 18:11 [entrez]
AID - S0946-672X(23)00183-9 [pii]
AID - 10.1016/j.jtemb.2023.127307 [doi]
PST - ppublish
SO  - J Trace Elem Med Biol. 2023 Dec;80:127307. doi: 10.1016/j.jtemb.2023.127307. Epub 
      2023 Sep 18.