| dc.contributor.advisor | Dobbelstein, Matthias Prof. Dr. | |
| dc.contributor.author | Sriraman, Anusha | |
| dc.date.accessioned | 2018-09-19T13:09:38Z | |
| dc.date.available | 2018-09-19T13:09:38Z | |
| dc.date.issued | 2018-09-19 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-002E-E4AB-3 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7056 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Targeting MDM2, the antagonist of the tumor suppressor p53 | de |
| dc.type | cumulativeThesis | de |
| dc.contributor.referee | Dobbelstein, Matthias Prof. Dr. | |
| dc.date.examination | 2018-09-10 | |
| dc.description.abstracteng | p53 is one of the most extensively studied tumor suppressor proteins, and its gene is mutated in 50% of human cancers. Stress signals activate p53 and its transcriptional machinery which lead to cell-cycle arrest, apoptosis or senescence. MDM2, its target gene product and the main negative regulator can bind to p53, and mark it for proteasomal degradation via its RING finger domain and the associated E3 ubiquitin ligase activity. Preventing the p53-MDM2 interaction via small molecule inhibitors appears to be the most obvious strategy to eliminate tumors harboring wild-type p53. However, despite extensive research, clinical responses to these drugs have been disappointing. Patient studies do not indicate durable tumor regression upon administration of these drugs but rendered adverse effects like nausea, vomiting, diarrhea and hematological disorders such as neutropenia and thrombocytopenia.
In this thesis, we have aimed to evaluate MDM2 inhibitors in combination with other drugs that lead to either synergism or antagonism with respect to p53 response in three diverse manners.
Firstly, we have utilized the concept of cyclotherapy and MDM2 inhibition to protect normal cells against agents like WEE1 inhibitors that causes replicative stress. We have found that pre-treatment of cells with MDM2 inhibitors shielded them from cytotoxic effects of WEE1 inhibition. This strategy would be beneficial in the clinics to target p53-deficient cancer cells, while protecting the p53-wild-type normal cells. Secondly, we targeted the two negative regulators of p53, namely MDM2 and WIP1 by inhibitors to enhance cellular cytotoxicity. This led to an increased expression and occupancy of p53 at its target genes and also caused a senescent phenotype. Finally, we observed an unexpected antagonism between inhibitors of MDM2 and CDK4/6 regarding cell viability and p53 response, indicating CDK4 is a supportive kinase for p53 activity.
Thus, our studies indicate three different approaches to modulate the cytotoxic effects of MDM2 inhibition. Taken together from our observations, we conclude that MDM2 inhibition might lead to patient benefit by changing the purpose of the drug; by combining it with other drugs that can mediate stronger toxicity; and lastly by targeting the correct population of tumors to obtain robust effects. | de |
| dc.contributor.coReferee | Johnsen, Steven Prof. Dr. | |
| dc.subject.eng | p53+ MDM2+ Nutlin+ WEE1+ gemcitabine+ WIP1+ CDK4+ | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-002E-E4AB-3-6 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 1031095721 | |