PMID- 34800614
OWN - NLM
STAT- MEDLINE
DCOM- 20220111
LR  - 20220216
IS  - 1879-3169 (Electronic)
IS  - 0378-4274 (Print)
IS  - 0378-4274 (Linking)
VI  - 355
DP  - 2022 Feb 1
TI  - Manganese phosphorylates Yin Yang 1 at serine residues to repress EAAT2 in human 
      H4 astrocytes.
PG  - 41-46
LID - S0378-4274(21)00883-3 [pii]
LID - 10.1016/j.toxlet.2021.11.007 [doi]
AB  - Impairment of the astrocytic glutamate transporter excitatory amino acid 
      transporter 2 (EAAT2) is associated with neurological disorders such as 
      Parkinson's disease (PD), Alzheimer's disease (AD), and manganism, a neurological 
      disorder caused by overexposure to manganese (Mn) which shares the features of 
      sporadic PD. Mechanisms of Mn-induced neurotoxicity include dysregulation of 
      EAAT2 following activation of the transcription factor Yin Yang 1 (YY1) by 
      transcriptional upregulation, but the posttranslational mechanisms by which YY1 
      is activated to repress EAAT2 remain to be elucidated. In the present study, we 
      tested if Mn activates YY1 through posttranslational phosphorylation in cultured 
      H4 human astrocytes, leading to EAAT2 repression. The results demonstrate that Mn 
      exposure induced phosphorylation of YY1 at serine residues via kinases Aurora B 
      kinase (AurkB) and Casein kinase II (CK2), leading to YY1 nuclear translocation, 
      YY1/HDAC interactions, binding to the EAAT2 promoter, and consequent decreases in 
      EAAT2 promoter activity and mRNA/protein levels. Although further studies are 
      warranted to fully elucidate the mechanisms of Mn-induced YY1 phosphorylation and 
      resultant EAAT2 impairment, our findings indicate that serine phosphorylation of 
      YY1 via AurkB and CK2 is critical, at least in part, to its activation and 
      transcriptional repression of EAAT2.
CI  - Copyright (c) 2021. Published by Elsevier B.V.
FAU - Rizor, Asha
AU  - Rizor A
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M 
      University, Tallahassee, FL, 32301, USA.
FAU - Pajarillo, Edward
AU  - Pajarillo E
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M 
      University, Tallahassee, FL, 32301, USA.
FAU - Son, Deok-Soo
AU  - Son DS
AD  - Department of Biochemistry and Cancer Biology, Meharry Medical College, 
      Nashville, TN, 37208, USA.
FAU - Aschner, Michael
AU  - Aschner M
AD  - Department of Molecular Pharmacology, Albert Einstein College of Medicine Bronx, 
      New York, NY, 10461, USA; Sechenov First Moscow State Medical University, Moscow, 
      Russia.
FAU - Lee, Eunsook
AU  - Lee E
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M 
      University, Tallahassee, FL, 32301, USA. Electronic address: 
      eunsook.lee@famu.edu.
LA  - eng
GR  - U54 MD007582/MD/NIMHD NIH HHS/United States
GR  - SC1 CA200519/CA/NCI NIH HHS/United States
GR  - R01 ES020852/ES/NIEHS NIH HHS/United States
GR  - R01 ES024756/ES/NIEHS NIH HHS/United States
GR  - R01 ES031282/ES/NIEHS NIH HHS/United States
GR  - R01 ES007331/ES/NIEHS NIH HHS/United States
GR  - R01 ES010563/ES/NIEHS NIH HHS/United States
PT  - Journal Article
DEP - 20211117
PL  - Netherlands
TA  - Toxicol Lett
JT  - Toxicology letters
JID - 7709027
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (SLC1A2 protein, human)
RN  - 0 (YY1 Transcription Factor)
RN  - 42Z2K6ZL8P (Manganese)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.1.11 (Checkpoint Kinase 2)
RN  - EC 2.7.11.1 (AURKB protein, human)
RN  - EC 2.7.11.1 (Aurora Kinase B)
RN  - EC 2.7.11.1 (CHEK2 protein, human)
SB  - IM
MH  - Amino Acid Sequence
MH  - Astrocytes/*drug effects/metabolism
MH  - Aurora Kinase B/genetics/metabolism
MH  - Cell Line
MH  - Checkpoint Kinase 2/genetics/metabolism
MH  - Excitatory Amino Acid Transporter 2/genetics/*metabolism
MH  - Gene Expression Regulation/*drug effects
MH  - Humans
MH  - Manganese/*pharmacology
MH  - Phosphorylation
MH  - Serine/chemistry
MH  - YY1 Transcription Factor/genetics/*metabolism
PMC - PMC8713424
MID - NIHMS1762589
OTO - NOTNLM
OT  - AurkB
OT  - CK2
OT  - EAAT2
OT  - Manganese
OT  - YY1
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2021/11/21 06:00
MHDA- 2022/01/12 06:00
PMCR- 2022/02/01
CRDT- 2021/11/20 20:12
PHST- 2021/08/06 00:00 [received]
PHST- 2021/10/25 00:00 [revised]
PHST- 2021/11/16 00:00 [accepted]
PHST- 2021/11/21 06:00 [pubmed]
PHST- 2022/01/12 06:00 [medline]
PHST- 2021/11/20 20:12 [entrez]
PHST- 2022/02/01 00:00 [pmc-release]
AID - S0378-4274(21)00883-3 [pii]
AID - 10.1016/j.toxlet.2021.11.007 [doi]
PST - ppublish
SO  - Toxicol Lett. 2022 Feb 1;355:41-46. doi: 10.1016/j.toxlet.2021.11.007. Epub 2021 
      Nov 17.