International journal of molecular sciences, 2022-02, Vol.23 (4), p.1994
2022
Details
- Autor(en) / Beteiligte
- Titel
- Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway
- Ist Teil von
- International journal of molecular sciences, 2022-02, Vol.23 (4), p.1994
- Ort / Verlag
- Switzerland: MDPI AG
- Erscheinungsjahr
- 2022
- Link zum Volltext
- Quelle
- EZB Free E-Journals
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1422-0067, 1661-6596eISSN: 1422-0067DOI: 10.3390/ijms23041994Titel-ID: cdi_doaj_primary_oai_doaj_org_article_d679ed45bd9b4234820274999e92ccb6
- Format
- –
- Schlagworte
- Affinity, Amino acids, Binding sites, Cancer, cancer mutation, Cell Line, Computer applications, Dipeptidyl-peptidase III, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - genetics, Domains, DPP III, Enzymes, Gene expression, Genomes, HEK293 Cells, Humans, Interdisciplinary aspects, Interdisciplinary Studies, KEAP1-NRF2 pathway, Kelch-Like ECH-Associated Protein 1 - genetics, Molecular biology, Molecular modelling, Multiple myeloma, Mutation, Mutation - genetics, Neoplasms - genetics, NF-E2-Related Factor 2 - genetics, Oxidative stress, Oxidative Stress - genetics, Peptidase, Peptidases, protein interaction, Proteins, Signal transduction, Signal Transduction - genetics, Transcription, Transcription, Genetic - genetics, Tumors