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Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway

Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
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Academic Editor: Eun-Hee Kim
Int. J. Mol. Sci. 2022, 23(4), 1994; https://doi.org/10.3390/ijms23041994
Received: 31 December 2021 / Revised: 2 February 2022 / Accepted: 8 February 2022 / Published: 11 February 2022
(This article belongs to the Special Issue Role of Nrf2/Keap1 Signaling Pathway in Human Diseases)
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. View Full-Text
Keywords: DPP III; KEAP1-NRF2 pathway; oxidative stress; cancer mutation; protein interaction DPP III; KEAP1-NRF2 pathway; oxidative stress; cancer mutation; protein interaction
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MDPI and ACS Style

Matić, S.; Tomašić Paić, A.; Sobočanec, S.; Pinterić, M.; Pipalović, G.; Martinčić, M.; Matovina, M.; Tomić, S. Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway. Int. J. Mol. Sci. 2022, 23, 1994. https://doi.org/10.3390/ijms23041994

AMA Style

Matić S, Tomašić Paić A, Sobočanec S, Pinterić M, Pipalović G, Martinčić M, Matovina M, Tomić S. Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway. International Journal of Molecular Sciences. 2022; 23(4):1994. https://doi.org/10.3390/ijms23041994

Chicago/Turabian Style

Matić, Sara, Ana Tomašić Paić, Sandra Sobočanec, Marija Pinterić, Goran Pipalović, Monika Martinčić, Mihaela Matovina, and Sanja Tomić. 2022. "Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway" International Journal of Molecular Sciences 23, no. 4: 1994. https://doi.org/10.3390/ijms23041994

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