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Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks
There is hitherto no literature available for explaining two distinct, but confused, Nrf1 transcription factors, because they shared the same abbreviations from nuclear factor erythroid 2-related factor 1 (also called Nfe2l1) and nuclear respiratory factor (originally designated α-Pal). Thus, we hav...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Hindawi
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744186/ https://www.ncbi.nlm.nih.gov/pubmed/33376579 http://dx.doi.org/10.1155/2020/5097109 |
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author | Zhang, Shuwei Deng, Yangxu Xiang, Yuancai Hu, Shaofan Qiu, Lu Zhang, Yiguo |
author_facet | Zhang, Shuwei Deng, Yangxu Xiang, Yuancai Hu, Shaofan Qiu, Lu Zhang, Yiguo |
author_sort | Zhang, Shuwei |
collection | PubMed |
description | There is hitherto no literature available for explaining two distinct, but confused, Nrf1 transcription factors, because they shared the same abbreviations from nuclear factor erythroid 2-related factor 1 (also called Nfe2l1) and nuclear respiratory factor (originally designated α-Pal). Thus, we have here identified that Nfe2l1(Nrf1) and α-Pal(NRF1) exert synergistic and antagonistic roles in integrative regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription profiles. In mouse embryonic fibroblasts (MEFs), knockout of Nfe2l1(−/−) leads to substantial decreases in expression levels of α-Pal(NRF1) and Nfe2l2, together with TFAM (mitochondrial transcription factor A) and other target genes. Similar inhibitory results were determined in Nfe2l2(−/−) MEFs but with an exception that both GSTa1 and Aldh1a1 were distinguishably upregulated in Nfe2l1(−/−) MEFs. Such synergistic contributions of Nfe2l1 and Nfe2l2 to the positive regulation of α-Pal(NRF1) and TFAM were validated in Keap1(−/−) MEFs. However, human α-Pal(NRF1) expression was unaltered by hNfe2l1α(−/−), hNfe2l2(-/-ΔTA), or even hNfe2l1α(−/−)+siNrf2, albeit TFAM was activated by Nfe2l1 but inhibited by Nfe2l2; such an antagonism occurred in HepG2 cells. Conversely, almost all of mouse Nfe2l1, Nfe2l2, and cotarget genes were downexpressed in α-Pal(NRF1+/-) MEFs. On the contrary, upregulation of human Nfe2l1, Nfe2l2, and relevant reporter genes took place after silencing of α-Pal(NRF1), but their downregulation occurred upon ectopic expression of α-Pal(NRF1). Furtherly, Pitx2 (pituitary homeobox 2) was also identified as a direct upstream regulator of Nfe2l1 and TFAM, besides α-Pal(NRF1). Overall, these across-talks amongst Nfe2l1, Nfe2l2, and α-Pal(NRF1), along with Pitx2, are integrated from the endoplasmic reticulum towards the nuclear-to-mitochondrial communication for targeting TFAM, in order to finely tune the robust balance of distinct cellular oxidative respiratory and antioxidant gene transcription networks, albeit they differ between the mouse and the human. In addition, it is of crucial importance to note that, in view of such mutual interregulation of these transcription factors, much cautions should be severely taken for us to interpret those relevant experimental results obtained from knockout of Nfe2l1, Nfe2l2, α-Pal or Pitx2, or their gain-of-functional mutants. |
format | Online Article Text |
id | pubmed-7744186 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-77441862020-12-28 Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks Zhang, Shuwei Deng, Yangxu Xiang, Yuancai Hu, Shaofan Qiu, Lu Zhang, Yiguo Oxid Med Cell Longev Research Article There is hitherto no literature available for explaining two distinct, but confused, Nrf1 transcription factors, because they shared the same abbreviations from nuclear factor erythroid 2-related factor 1 (also called Nfe2l1) and nuclear respiratory factor (originally designated α-Pal). Thus, we have here identified that Nfe2l1(Nrf1) and α-Pal(NRF1) exert synergistic and antagonistic roles in integrative regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription profiles. In mouse embryonic fibroblasts (MEFs), knockout of Nfe2l1(−/−) leads to substantial decreases in expression levels of α-Pal(NRF1) and Nfe2l2, together with TFAM (mitochondrial transcription factor A) and other target genes. Similar inhibitory results were determined in Nfe2l2(−/−) MEFs but with an exception that both GSTa1 and Aldh1a1 were distinguishably upregulated in Nfe2l1(−/−) MEFs. Such synergistic contributions of Nfe2l1 and Nfe2l2 to the positive regulation of α-Pal(NRF1) and TFAM were validated in Keap1(−/−) MEFs. However, human α-Pal(NRF1) expression was unaltered by hNfe2l1α(−/−), hNfe2l2(-/-ΔTA), or even hNfe2l1α(−/−)+siNrf2, albeit TFAM was activated by Nfe2l1 but inhibited by Nfe2l2; such an antagonism occurred in HepG2 cells. Conversely, almost all of mouse Nfe2l1, Nfe2l2, and cotarget genes were downexpressed in α-Pal(NRF1+/-) MEFs. On the contrary, upregulation of human Nfe2l1, Nfe2l2, and relevant reporter genes took place after silencing of α-Pal(NRF1), but their downregulation occurred upon ectopic expression of α-Pal(NRF1). Furtherly, Pitx2 (pituitary homeobox 2) was also identified as a direct upstream regulator of Nfe2l1 and TFAM, besides α-Pal(NRF1). Overall, these across-talks amongst Nfe2l1, Nfe2l2, and α-Pal(NRF1), along with Pitx2, are integrated from the endoplasmic reticulum towards the nuclear-to-mitochondrial communication for targeting TFAM, in order to finely tune the robust balance of distinct cellular oxidative respiratory and antioxidant gene transcription networks, albeit they differ between the mouse and the human. In addition, it is of crucial importance to note that, in view of such mutual interregulation of these transcription factors, much cautions should be severely taken for us to interpret those relevant experimental results obtained from knockout of Nfe2l1, Nfe2l2, α-Pal or Pitx2, or their gain-of-functional mutants. Hindawi 2020-11-16 /pmc/articles/PMC7744186/ /pubmed/33376579 http://dx.doi.org/10.1155/2020/5097109 Text en Copyright © 2020 Shuwei Zhang et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Zhang, Shuwei Deng, Yangxu Xiang, Yuancai Hu, Shaofan Qiu, Lu Zhang, Yiguo Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks |
title | Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks |
title_full | Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks |
title_fullStr | Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks |
title_full_unstemmed | Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks |
title_short | Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks |
title_sort | synergism and antagonism of two distinct, but confused, nrf1 factors in integral regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription networks |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744186/ https://www.ncbi.nlm.nih.gov/pubmed/33376579 http://dx.doi.org/10.1155/2020/5097109 |
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