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Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells

APE1/Ref-1 (apurinic/apyrimidinic endonuclease 1, APE1 or APEX1; redox factor-1, Ref-1) is a dual-functional enzyme with crucial roles in DNA repair, reduction/oxidation (redox) signaling, and RNA processing and metabolism. The redox function of Ref-1 regulates several transcription factors, such as...

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Autores principales: Mijit, Mahmut, Liu, Sheng, Sishtla, Kamakshi, Hartman, Gabriella D., Wan, Jun, Corson, Timothy W., Kelley, Mark R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865623/
https://www.ncbi.nlm.nih.gov/pubmed/36674619
http://dx.doi.org/10.3390/ijms24021101
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author Mijit, Mahmut
Liu, Sheng
Sishtla, Kamakshi
Hartman, Gabriella D.
Wan, Jun
Corson, Timothy W.
Kelley, Mark R.
author_facet Mijit, Mahmut
Liu, Sheng
Sishtla, Kamakshi
Hartman, Gabriella D.
Wan, Jun
Corson, Timothy W.
Kelley, Mark R.
author_sort Mijit, Mahmut
collection PubMed
description APE1/Ref-1 (apurinic/apyrimidinic endonuclease 1, APE1 or APEX1; redox factor-1, Ref-1) is a dual-functional enzyme with crucial roles in DNA repair, reduction/oxidation (redox) signaling, and RNA processing and metabolism. The redox function of Ref-1 regulates several transcription factors, such as NF-κB, STAT3, HIF-1α, and others, which have been implicated in multiple human diseases, including ocular angiogenesis, inflammation, and multiple cancers. To better understand how APE1 influences these disease processes, we investigated the effects of APEX1 knockdown (KD) on gene expression in human retinal endothelial cells. This abolishes both DNA repair and redox signaling functions, as well as RNA interactions. Using RNA-seq analysis, we identified the crucial signaling pathways affected following APEX1 KD, with subsequent validation by qRT-PCR. Gene expression data revealed that multiple genes involved in DNA base excision repair, other DNA repair pathways, purine or pyrimidine metabolism signaling, and histidine/one carbon metabolism pathways were downregulated by APEX1 KD. This is in contrast with the alteration of pathways by APEX1 KD in human cancer lines, such as pancreatic ductal adenocarcinoma, lung, HeLa, and malignant peripheral nerve sheath tumors. These results highlight the unique role of APE1/Ref-1 and the clinical therapeutic potential of targeting APE1 and pathways regulated by APE1 in the eye. These findings provide novel avenues for ocular neovascularization treatment.
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spelling pubmed-98656232023-01-22 Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells Mijit, Mahmut Liu, Sheng Sishtla, Kamakshi Hartman, Gabriella D. Wan, Jun Corson, Timothy W. Kelley, Mark R. Int J Mol Sci Article APE1/Ref-1 (apurinic/apyrimidinic endonuclease 1, APE1 or APEX1; redox factor-1, Ref-1) is a dual-functional enzyme with crucial roles in DNA repair, reduction/oxidation (redox) signaling, and RNA processing and metabolism. The redox function of Ref-1 regulates several transcription factors, such as NF-κB, STAT3, HIF-1α, and others, which have been implicated in multiple human diseases, including ocular angiogenesis, inflammation, and multiple cancers. To better understand how APE1 influences these disease processes, we investigated the effects of APEX1 knockdown (KD) on gene expression in human retinal endothelial cells. This abolishes both DNA repair and redox signaling functions, as well as RNA interactions. Using RNA-seq analysis, we identified the crucial signaling pathways affected following APEX1 KD, with subsequent validation by qRT-PCR. Gene expression data revealed that multiple genes involved in DNA base excision repair, other DNA repair pathways, purine or pyrimidine metabolism signaling, and histidine/one carbon metabolism pathways were downregulated by APEX1 KD. This is in contrast with the alteration of pathways by APEX1 KD in human cancer lines, such as pancreatic ductal adenocarcinoma, lung, HeLa, and malignant peripheral nerve sheath tumors. These results highlight the unique role of APE1/Ref-1 and the clinical therapeutic potential of targeting APE1 and pathways regulated by APE1 in the eye. These findings provide novel avenues for ocular neovascularization treatment. MDPI 2023-01-06 /pmc/articles/PMC9865623/ /pubmed/36674619 http://dx.doi.org/10.3390/ijms24021101 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mijit, Mahmut
Liu, Sheng
Sishtla, Kamakshi
Hartman, Gabriella D.
Wan, Jun
Corson, Timothy W.
Kelley, Mark R.
Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells
title Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells
title_full Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells
title_fullStr Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells
title_full_unstemmed Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells
title_short Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells
title_sort identification of novel pathways regulated by ape1/ref-1 in human retinal endothelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865623/
https://www.ncbi.nlm.nih.gov/pubmed/36674619
http://dx.doi.org/10.3390/ijms24021101
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