PMID- 36933848
OWN - NLM
STAT- MEDLINE
DCOM- 20230513
LR  - 20231213
IS  - 1879-260X (Electronic)
IS  - 0925-4439 (Linking)
VI  - 1869
IP  - 5
DP  - 2023 Jun
TI  - Regulation of peroxiredoxin-3 gene expression under basal and hyperglycemic 
      conditions: Key roles for transcription factors Sp1, CREB and NF-kappaB.
PG  - 166691
LID - S0925-4439(23)00057-1 [pii]
LID - 10.1016/j.bbadis.2023.166691 [doi]
AB  - Peroxiredoxin-3 (Prx-3), a thioredoxin-dependent peroxidase located exclusively 
      in the mitochondrial matrix, catalyses peroxides/peroxinitrites. Altered levels 
      of Prx-3 is associated with diabetic cardiomyopathy (DCM). However, molecular 
      mechanisms of Prx-3 gene regulation remain partially understood. We undertook a 
      systemic analysis of the Prx-3 gene to identify the key motifs and 
      transcriptional regulatory molecules. Transfection of promoter-reporter 
      constructs in the cultured cells identified -191/+20 bp domain as the core 
      promoter region. Stringent in silico analysis of this core promoter revealed 
      putative binding sites for specificity protein 1 (Sp1), cAMP response 
      element-binding protein (CREB) and nuclear factor kappa-light-chain-enhancer of 
      activated B cells (NF-kappaB). Interestingly, while co-transfection of the 
      -191/+20 bp construct with Sp1/CREB plasmid diminished Prx3 promoter-reporter 
      activity, mRNA and protein levels, co-transfection with NF-kappaB expression plasmid 
      augmented the same. Consistently, inhibition of Sp1/CREB/NF-kappaB expression 
      reversed the promoter-reporter activity, mRNA and protein levels of Prx-3, 
      thereby confirming their regulatory effects. ChIP assays provided evidence for 
      interactions of Sp1/CREB/NF-kappaB with the Prx-3 promoter. H9c2 cells treated with 
      high glucose as well as streptozotocin (STZ)-treated diabetic rats showed 
      time-dependent reduction in promoter activity, endogenous transcript and protein 
      levels of Prx-3. Augmentation of Sp1/CREB protein levels and their strong binding 
      with Prx-3 promoter are responsible for diminished Prx-3 levels under 
      hyperglycemia. The activation/increase in the NF-kappaB expression under 
      hyperglycemia was not sufficient to restore the reduction of endogenous Prx-3 
      levels owing to its weak binding affinity. Taken together, this study elucidates 
      the previously unknown roles of Sp1/CREB/NF-kappaB in regulating Prx-3 gene 
      expression under hyperglycemic condition.
CI  - Copyright (c) 2023 Elsevier B.V. All rights reserved.
FAU - Arkat, Silpa
AU  - Arkat S
AD  - Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian 
      Institute of Technology Madras, Chennai 600036, India.
FAU - Poovitha, Sundar
AU  - Poovitha S
AD  - Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian 
      Institute of Technology Madras, Chennai 600036, India.
FAU - Vijayakumar, Anupama
AU  - Vijayakumar A
AD  - Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian 
      Institute of Technology Madras, Chennai 600036, India.
FAU - Dhat, Rohini
AU  - Dhat R
AD  - National Centre for Cell Science, NCCS Complex, S.P. Pune University, 
      Ganeshkhind, Pune 411007, Maharashtra, India.
FAU - Sitasawad, Sandhya L
AU  - Sitasawad SL
AD  - National Centre for Cell Science, NCCS Complex, S.P. Pune University, 
      Ganeshkhind, Pune 411007, Maharashtra, India.
FAU - Mahapatra, Nitish R
AU  - Mahapatra NR
AD  - Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian 
      Institute of Technology Madras, Chennai 600036, India. Electronic address: 
      nmahapatra@iitm.ac.in.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230316
PL  - Netherlands
TA  - Biochim Biophys Acta Mol Basis Dis
JT  - Biochimica et biophysica acta. Molecular basis of disease
JID - 101731730
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (NF-kappa B)
RN  - EC 1.11.1.15 (Peroxiredoxin III)
RN  - 0 (RNA, Messenger)
RN  - 0 (Creb1 protein, rat)
RN  - 0 (Sp1 Transcription Factor)
SB  - IM
MH  - Animals
MH  - Rats
MH  - Cyclic AMP Response Element-Binding Protein/genetics/metabolism
MH  - *Diabetes Mellitus, Experimental/genetics
MH  - Gene Expression
MH  - *NF-kappa B/genetics/metabolism
MH  - Peroxiredoxin III/genetics
MH  - RNA, Messenger/metabolism
MH  - Sp1 Transcription Factor
OTO - NOTNLM
OT  - Diabetic cardiomyopathy
OT  - Gene regulation
OT  - Heart
OT  - Mitochondria
OT  - Peroxiredoxin-3
OT  - Streptozotocin
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- 2023/03/19 06:00
MHDA- 2023/05/08 10:17
CRDT- 2023/03/18 20:32
PHST- 2022/12/13 00:00 [received]
PHST- 2023/02/27 00:00 [revised]
PHST- 2023/03/10 00:00 [accepted]
PHST- 2023/05/08 10:17 [medline]
PHST- 2023/03/19 06:00 [pubmed]
PHST- 2023/03/18 20:32 [entrez]
AID - S0925-4439(23)00057-1 [pii]
AID - 10.1016/j.bbadis.2023.166691 [doi]
PST - ppublish
SO  - Biochim Biophys Acta Mol Basis Dis. 2023 Jun;1869(5):166691. doi: 
      10.1016/j.bbadis.2023.166691. Epub 2023 Mar 16.