| dc.contributor.advisor | Wienands, Jürgen Prof. Dr. | |
| dc.contributor.author | Mayr, Florian | |
| dc.date.accessioned | 2023-11-23T17:55:42Z | |
| dc.date.available | 2023-11-30T00:50:09Z | |
| dc.date.issued | 2023-11-23 | |
| dc.identifier.uri | http://resolver.sub.uni-goettingen.de/purl?ediss-11858/14992 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-10219 | |
| dc.format.extent | 185 | de |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | The enzymatic product of SH2 domain-containing inositol 5-phosphatases supports the fitness of BCR-dependent Burkitt lymphoma cells by promoting the energy metabolism | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Wienands, Jürgen Prof. Dr. | |
| dc.date.examination | 2023-11-13 | de |
| dc.description.abstracteng | Burkitt lymphoma (BL) is an aggressively growing neoplasm owing to an over expression
of the MYC oncogene and exploitation of the tonic B cell receptor (BCR) signaling for its
survival. While it is known that the survival signaling is mediated by the phosphoinositide-
3-kinase (PI3K), the details of the rewired BL-specific BCR signaling network remain
poorly understood. A small-hairpin RNA (shRNA) based loss of function screen revealed
that the SH2 domain-containing 5-inositol phosphatase 2 (SHIP2) potentially influences
the survival of BL cells. Generation and characterisation of multiple SHIP2-deficient
BL cell lines revealed a perturbed proliferation and increased apoptosis. Furthermore,
these effects could not be observed in a surface BCR-negative BL cell line, suggesting
that SHIP2 activity is regulated by tonic BCR signaling. SHIP2 is generally described as
a negative regulator of AKT activity, but the phosphorylation levels of AKT remained
stable in the absence of SHIP2. Similarly, the activation of mitogen-activated protein
kinases (MAPK) were unaltered. In contrast, SHIP2 deficiency attenuated the ATP
production independently of glucose uptake. It was found that the enzymatic product
of SHIP2, phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2), is required for an efficient
energy metabolism. In addition, SHIP2-deficient cells exhibited lowered aspartate levels,
possibly due to inefficient glycolysis. Further, interference with the function of SHIP1
mirrored the effects observed in SHIP2-deficient cells, indicating a redundant function.
Consistently, interruption of SHIP1/2 activity in BL cell lines augmented the susceptibility
to inhibition of survival signaling mediated by the PI3K. This study provides a molecular
basis describing how tonic BCR signals are linked to an efficient energy metabolism,
which is particularly necessary to fuel a fast growing tumor such as BL. Moreover, these
discoveries may serve as a basis to potentially enhance the treatment efficiency of BL by
targeting the energy supply through the inhibition of SHIP proteins, thus increasing the
vulnerability to targeting survival signals. | de |
| dc.contributor.coReferee | Faesen, Alex Caspar Dr. | |
| dc.subject.eng | Immunology | de |
| dc.subject.eng | Burkitt Lymphoma | de |
| dc.subject.eng | B cell receptor | de |
| dc.subject.eng | Signal Transduction | de |
| dc.subject.eng | Inositol phosphatase | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-ediss-14992-6 | |
| dc.affiliation.institute | Biologische Fakultät für Biologie und Psychologie | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.description.embargoed | 2023-11-30 | de |
| dc.identifier.ppn | 1871667437 | |
| dc.notes.confirmationsent | Confirmation sent 2023-11-23T19:45:01 | de |