hrvatski jezikClear Cookie - decide language by browser settings

Interdisciplinary study of the effects of dipeptidyl-peptidase III cancer mutations on the KEAP1-NRF2 signaling pathway

Matić, Sara; Tomašić Paić, Ana; Sobočanec, Sandra; Pinterić, Marija; Pipalović, Goran; Martinčić, Monika; Matovina, Mihaela; Tomić, Sanja (2022) Interdisciplinary study of the effects of dipeptidyl-peptidase III cancer mutations on the KEAP1-NRF2 signaling pathway. International journal of molecular sciences, 23 (4). ISSN 1422-0067

PDF - Published Version - article
Available under License Creative Commons Attribution.

Download (2MB) | Preview


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.

Item Type: Article
Uncontrolled Keywords: DPP III ; KEAP1-NRF2 pathway ; oxidative stress ; cancer mutation ; protein interaction
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Division of Molecular Medicine
Division of Organic Chemistry and Biochemistry
Division of Physical Chemistry
Project titleProject leaderProject codeProject type
Biološka važnost dipeptidil peptidaze III i njezin utjecaj na zdravlje čovjekaTomić, SanjaIP-2018-01-2936HRZZ
Depositing User: Sara Matić
Date Deposited: 25 Mar 2022 08:11
DOI: 10.3390/ijms23041994

Actions (login required)

View Item View Item


Downloads per month over past year

Increase Font
Decrease Font
Dyslexic Font