| dc.contributor.advisor | Dobbelstein, Matthias Prof. Dr. | |
| dc.contributor.author | Wienken, Maria Magdalena | |
| dc.date.accessioned | 2016-01-22T09:46:41Z | |
| dc.date.available | 2016-01-22T09:46:41Z | |
| dc.date.issued | 2016-01-22 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0028-869F-7 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-5475 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | A regulatory network of Mdm2 and members of the Polycomb Group (PcG) family | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Halyna, Shcherbata Dr. | |
| dc.date.examination | 2016-01-10 | |
| dc.description.abstracteng | The E3 ubiquitin ligase MDM2 is the most well-known physiological antagonist of the tumor suppressor P53. P53 induces cell cycle arrest or apoptosis in the case of DNA damage, whereas MDM2 targets it for proteasomal degradation during unstressed conditions. Loss of MDM2 in the murine organism is embryonically lethal but can be rescued by a concomitant loss of P53, which led to the assumption that MDM2’s only function is based on P53 regulation. Still, several tumor species have been identified which are supported by high levels of MDM2 even in the absence of P53.
In this project, we have analyzed a P53-independent and stemness maintaining function of MDM2 which supported the de-differentiation process of induced pluripotent stem (iPS) cells. It furthermore inhibited differentiation of mesenchymal stem cells (MSCs) into osteoblasts and accelerated clonogenic cancer cell survival in the absence of P53. In each system, loss of MDM2 resulted in the deregulation of Polycomb group (PcG) family target genes. The PcG consists of the two protein complexes, PRC1 and PRC2, and silences gene expression through methylation of histone H3K27 (PRC2) and ubiquitination of H2AK119 (PRC1), which is often essential for stemness maintenance and cancer cell survival. MDM2 directly interacted with the PRC2 proteins EZH2 and SUZ12 and was recruited to PcG target gene promoters through EZH2. On the chromatin, MDM2 enhanced H3K27me3 and H2AK119ub1 which correlated to its gene regulatory function. H2AK119 is mainly ubiquitinated by the PRC1 protein RING1B. Loss of both E3 ligases, MDM2 and RING1B, decreased H2AK119ub1 levels and induced target gene expression further than the loss of each factor alone. Moreover, loss of RING1B and MDM2 was synthetically lethal in primary mouse- and cancer cells.
A close homolog of the MDM2 protein is MDM4. MDM2 and MDM4 support each other in the regulation of P53 but they cannot compensate each other according to in vivo loss of function studies. Preliminary data in our setting indicated a similar gene regulatory and H3K27me3 stabilizing function of MDM4 as detected for MDM2.
Taken together, MDM proteins enhanced the repression of lineage specific genes in cooperation with the PcG family, in the absence of P53. Thus, the oncogenic function of MDMs is not limited to controlling P53, but extended to chromatin modification and a stem-like cell phenotype. | de |
| dc.contributor.coReferee | Zeisberg, Michael Prof. Dr. | |
| dc.subject.eng | Mdm2, p53, PcG family, H3K27me3, H2AK119ub1, stemness, cancer | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0028-869F-7-1 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 846366363 | |