Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway
Dipeptidyl peptidase III (DPP III) is associated with cancer progression via interaction with KEAP1, leading to upregulation of the KEAP1-NRF2 oxidative stress pathway. Numerous DPP III mutations have been found in human tumor genomes, and it is suggested that some of them may alter affinity for KEA...
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2022-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/4/1994 |
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| author | Sara Matić Ana Tomašić Paić Sandra Sobočanec Marija Pinterić Goran Pipalović Monika Martinčić Mihaela Matovina Sanja Tomić |
| author_facet | Sara Matić Ana Tomašić Paić Sandra Sobočanec Marija Pinterić Goran Pipalović Monika Martinčić Mihaela Matovina Sanja Tomić |
| author_sort | Sara Matić |
| collection | DOAJ |
| description | Dipeptidyl peptidase III (DPP III) is associated with cancer progression via interaction with KEAP1, leading to upregulation of the KEAP1-NRF2 oxidative stress pathway. Numerous DPP III mutations have been found in human tumor genomes, and it is suggested that some of them may alter affinity for KEAP1. One such example is the DPP III-R623W variant, which in our previous study showed much higher affinity for the Kelch domain of KEAP1 than the wild-type protein. In this work, we have investigated the effects of this mutation in cultured cells and the effects of several other DPP III mutations on the stability of KEAP1-DPP III complex using an interdisciplinary approach combining biochemical, biophysical and molecular biology methods with computational studies. We determined the affinity of the DPP III variants for the Kelch domain experimentally and by molecular modeling, as well as the effects of the R623W on the expression of several NRF2-controlled genes. We confirmed that the R623W variant upregulates NQO1 expression at the transcriptional level. This supports the hypothesis from our previous study that the increased affinity of the R623W variant for KEAP1 leads to upregulation of the KEAP1-NRF2 pathway. These results provide a new perspective on the involvement of DPP III in cancer progression and prognosis. |
| first_indexed | 2024-03-09T21:46:26Z |
| format | Article |
| id | doaj.art-d679ed45bd9b4234820274999e92ccb6 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:46:26Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d679ed45bd9b4234820274999e92ccb62023-11-23T20:18:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-02-01234199410.3390/ijms23041994Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling PathwaySara Matić0Ana Tomašić Paić1Sandra Sobočanec2Marija Pinterić3Goran Pipalović4Monika Martinčić5Mihaela Matovina6Sanja Tomić7Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, CroatiaRuđer Bošković Institute, Bijenička 54, 10000 Zagreb, CroatiaRuđer Bošković Institute, Bijenička 54, 10000 Zagreb, CroatiaRuđer Bošković Institute, Bijenička 54, 10000 Zagreb, CroatiaRuđer Bošković Institute, Bijenička 54, 10000 Zagreb, CroatiaRuđer Bošković Institute, Bijenička 54, 10000 Zagreb, CroatiaRuđer Bošković Institute, Bijenička 54, 10000 Zagreb, CroatiaRuđer Bošković Institute, Bijenička 54, 10000 Zagreb, CroatiaDipeptidyl peptidase III (DPP III) is associated with cancer progression via interaction with KEAP1, leading to upregulation of the KEAP1-NRF2 oxidative stress pathway. Numerous DPP III mutations have been found in human tumor genomes, and it is suggested that some of them may alter affinity for KEAP1. One such example is the DPP III-R623W variant, which in our previous study showed much higher affinity for the Kelch domain of KEAP1 than the wild-type protein. In this work, we have investigated the effects of this mutation in cultured cells and the effects of several other DPP III mutations on the stability of KEAP1-DPP III complex using an interdisciplinary approach combining biochemical, biophysical and molecular biology methods with computational studies. We determined the affinity of the DPP III variants for the Kelch domain experimentally and by molecular modeling, as well as the effects of the R623W on the expression of several NRF2-controlled genes. We confirmed that the R623W variant upregulates NQO1 expression at the transcriptional level. This supports the hypothesis from our previous study that the increased affinity of the R623W variant for KEAP1 leads to upregulation of the KEAP1-NRF2 pathway. These results provide a new perspective on the involvement of DPP III in cancer progression and prognosis.https://www.mdpi.com/1422-0067/23/4/1994DPP IIIKEAP1-NRF2 pathwayoxidative stresscancer mutationprotein interaction |
| spellingShingle | Sara Matić Ana Tomašić Paić Sandra Sobočanec Marija Pinterić Goran Pipalović Monika Martinčić Mihaela Matovina Sanja Tomić Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway International Journal of Molecular Sciences DPP III KEAP1-NRF2 pathway oxidative stress cancer mutation protein interaction |
| title | Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway |
| title_full | Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway |
| title_fullStr | Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway |
| title_full_unstemmed | Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway |
| title_short | Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway |
| title_sort | interdisciplinary study of the effects of dipeptidyl peptidase iii cancer mutations on the keap1 nrf2 signaling pathway |
| topic | DPP III KEAP1-NRF2 pathway oxidative stress cancer mutation protein interaction |
| url | https://www.mdpi.com/1422-0067/23/4/1994 |
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