Trombetti, Silvia (2022) Exploring the leukemogenic potential of GATA-1S, the shorter isoform of the hematopoietic transcriptional factor GATA-1, through mechanisms of mitochondrial remodeling, metabolic rewiring and apoptosis resistance associated with modulation of the cellular redox state. [Tesi di dottorato]
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| Item Type: | Tesi di dottorato |
|---|---|
| Resource language: | English |
| Title: | Exploring the leukemogenic potential of GATA-1S, the shorter isoform of the hematopoietic transcriptional factor GATA-1, through mechanisms of mitochondrial remodeling, metabolic rewiring and apoptosis resistance associated with modulation of the cellular redox state |
| Creators: | Creators Email Trombetti, Silvia Silvia.trombetti@unina.it |
| Date: | 10 March 2022 |
| Number of Pages: | 85 |
| Institution: | Università degli Studi di Napoli Federico II |
| Department: | Medicina Molecolare e Biotecnologie Mediche |
| Dottorato: | Medicina molecolare e biotecnologie mediche |
| Ciclo di dottorato: | 34 |
| Coordinatore del Corso di dottorato: | nome email Santoro, Massimo masantor@unina.it |
| Tutor: | nome email Grosso, Michela UNSPECIFIED |
| Date: | 10 March 2022 |
| Number of Pages: | 85 |
| Keywords: | leukemia, redox state, mitochondrial remodeling, GATA-1 |
| Settori scientifico-disciplinari del MIUR: | Area 05 - Scienze biologiche > BIO/10 - Biochimica |
| Date Deposited: | 17 Mar 2022 15:11 |
| Last Modified: | 28 Feb 2024 10:27 |
| URI: | http://www.fedoa.unina.it/id/eprint/14477 |
Collection description
Maintenance of a balanced expression of the two isoforms of the transcription factor GATA‐1, the full‐length protein (GATA‐1FL) and its shorter isoform (GATA‐1S), contributes to control hematopoiesis, whereas their dysregulation can alter the differentiation/proliferation potential of hematopoietic precursors thereby eventually leading to a variety of hematopoietic disorders. Although it is well established that these isoforms play opposite roles in these remarkable processes, most of the molecular pathways involved remain unknown. This thesis demonstrates that GATA‐1FL and GATA‐1S differentially influence mitochondrial remodeling, intracellular redox state and reactive oxygen species (ROS) compartmentation in K562 cell line and that the resistance to apoptosis in GATA-1S cells is directly related to enhanced antioxidant capacity associated with GATA-1S abnormal expression. GATA-1S over-expression has also been found to be associated with high levels of the succinate dehydrogenase subunit C (SDHC). Based on the evidence that SDHC is over-expressed in several tumors with alternative splicing variants acting as potent dominant negative inhibitors of Succinate dehydrogenase (SDH activity), the levels of SDHC variants and the rate of oxidative mitochondrial metabolism have been examined in K562 cells over-expressing GATA-1 isoforms. Over-expression of SDHC variants accompanied by decreased SDH complex II activity and oxidative phosphorylation (OXPHOS) efficiency was found associated only with GATA- 1S over-expression. Given the tumor suppressor role of SDH and the effects of OXPHOS limitations in leukemogenesis, identification of a link between GATA-1S and impaired complex II activity unveils novel pro-leukemic mechanisms triggered by GATA-1S. Abnormal levels of GATA-1S and SDHC variants were also found in an acute myeloid leukemia (AML) patient, thus supporting in vitro results. A better understanding of these mechanisms can contribute to identify novel promising therapeutic targets in myeloid leukemia.
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