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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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/2/1101 |
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| author | Mahmut Mijit Sheng Liu Kamakshi Sishtla Gabriella D. Hartman Jun Wan Timothy W. Corson Mark R. Kelley |
| author_facet | Mahmut Mijit Sheng Liu Kamakshi Sishtla Gabriella D. Hartman Jun Wan Timothy W. Corson Mark R. Kelley |
| author_sort | Mahmut Mijit |
| collection | DOAJ |
| 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 <i>APEX1</i> 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 <i>APEX1</i> 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 <i>APEX1</i> KD. This is in contrast with the alteration of pathways by <i>APEX1</i> 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. |
| first_indexed | 2024-03-09T12:25:30Z |
| format | Article |
| id | doaj.art-225f309b8fa440ffb04a66d1cd87bd86 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:25:30Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-225f309b8fa440ffb04a66d1cd87bd862023-11-30T22:35:27ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01242110110.3390/ijms24021101Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial CellsMahmut Mijit0Sheng Liu1Kamakshi Sishtla2Gabriella D. Hartman3Jun Wan4Timothy W. Corson5Mark R. Kelley6Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USAHerman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USAAPE1/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 <i>APEX1</i> 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 <i>APEX1</i> 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 <i>APEX1</i> KD. This is in contrast with the alteration of pathways by <i>APEX1</i> 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.https://www.mdpi.com/1422-0067/24/2/1101APE1/Ref-1redox signalingangiogenesisinflammationgene expressionocular diseases |
| spellingShingle | Mahmut Mijit Sheng Liu Kamakshi Sishtla Gabriella D. Hartman Jun Wan Timothy W. Corson Mark R. Kelley Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells International Journal of Molecular Sciences APE1/Ref-1 redox signaling angiogenesis inflammation gene expression ocular diseases |
| 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 | APE1/Ref-1 redox signaling angiogenesis inflammation gene expression ocular diseases |
| url | https://www.mdpi.com/1422-0067/24/2/1101 |
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