The deubiquitinase USP28 and its role in blood cell differentiation and cytokine signaling
Thesis event information
Date and time of the thesis defence
Place of the thesis defence
F101, Aapistie 7
Topic of the dissertation
The deubiquitinase USP28 and its role in blood cell differentiation and cytokine signaling
Doctoral candidate
Master of Science Elham Aryapour
Faculty and unit
University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, ECM and Hypoxia
Subject of study
Biochemistry and molecular biology
Opponent
Professor Lars-Oliver Klotz, University of Jena, Germany
Custos
Professor Thomas Kietzmann, University of Oulu
The deubiquitinase USP28 and its role in blood cell differentiation and cytokine signaling
Diseases like anemia, leukemia, lymphomas, and thrombocytopenia have been linked to disruptions in the hematopoietic system. Therefore, comprehending the molecular mechanisms that regulate the self-renewal and determination of cell fate in hematopoiesis is crucial for the advancement of clinical treatments tailored to specific diseases and their severity. Recent implementation of proteasome inhibitors such as bortezomib into clinical practice for treating hematopoietic cancers suggested that enzymes modulating proteasomal protein degradation such as the deubiquitinase USP28 may have a function during hematopoiesis and its regulation by cytokines. However, at current USP28´s role in these processes is unknown. Therefore, it was the aim of this work to gain a better understanding in USP28 and its role in blood cell differentiation and cytokine signaling.
The current study showed that USP28 has a role in bone formation along with blood cell differentiation. Further, the study showed that USP28 contributes to cytokine generation, NFkB activation and cell proliferation and migration. The lack of USP28 in bone marrow cells affected mainly cells from the myeloid lineage as well as T-cells. Thereby lack of USP28 was found to reduce apoptosis along with promotion of proliferation associated with expression of cell specific markers of the respective lineage. Interestingly, the effects on proliferation were not limited to hematopoietic cells as embryonic fibroblasts, skin derived cells as well as breast cancer cells showed similar features. In line, the reduced responsiveness of the NFkB transcription factor to TNFα and the decreased nuclear translocation appeared to occur in a cell-type independent manner. Therefore, USP28 has been proposed to be a potential therapeutic target for cancer treatment not limited to leukemia. However, more research is needed to fully understand the specific mechanisms by which USP28 regulates especially cell differentiation.
The current study showed that USP28 has a role in bone formation along with blood cell differentiation. Further, the study showed that USP28 contributes to cytokine generation, NFkB activation and cell proliferation and migration. The lack of USP28 in bone marrow cells affected mainly cells from the myeloid lineage as well as T-cells. Thereby lack of USP28 was found to reduce apoptosis along with promotion of proliferation associated with expression of cell specific markers of the respective lineage. Interestingly, the effects on proliferation were not limited to hematopoietic cells as embryonic fibroblasts, skin derived cells as well as breast cancer cells showed similar features. In line, the reduced responsiveness of the NFkB transcription factor to TNFα and the decreased nuclear translocation appeared to occur in a cell-type independent manner. Therefore, USP28 has been proposed to be a potential therapeutic target for cancer treatment not limited to leukemia. However, more research is needed to fully understand the specific mechanisms by which USP28 regulates especially cell differentiation.
Last updated: 23.1.2024