Characterizaton of the chromatin remodelling activity of the transcription factor c-Myb
Evolutionary Cell and Developmental Biology (Zoology)
Final Report Abstract
Myb is an oncogenic transcription factor that plays a key role in the hematopoietic system as a regulator of cell proliferation, differentiation and survival. In previous work we have identified a highly conserved region within the Myb transactivation domain that plays a crucial role in chromatin remodelling by Myb. In this project we have studied the interaction and functional consequences of proteins interacting with the chromatin remodelling domain. Our work demonstrates that this region mediates Myb-Myb self-interactions as well as interactions with TIP60, PRMT4 and Menin. We have shown that Myb self-interaction and binding of Tip60 interferes with the interaction between Myb and the co-activator p300, whose binding site is juxtaposed to the hydrophobic region, leading to inhibition of the activity of Myb. Interestingly, replacement of two valine residues by isoleucines strongly stimulates the interactions. In the second part of the project we have focused on small molecule inhibitors of Myb and their effects on protein-protein interactions mediated by the Myb transactivation domain, including the hydrophobic region. We have successfully identified several low-molecular weight compounds as inhibitors of Myb activity, thereby demonstrating for the first time that targeting of Myb by small molecule inhibitors is feasible. However, so far all the compounds that have been studied in sufficient detail act via inhibition of the interaction of Myb with p300.
Publications
- 2009. Myb-induced chromatin remodeling at a dual enhancer/promoter element involves non-coding RNA transcription and is disrupted by oncogenic mutations of v-myb. J. Biol. Chem. 284, 35314-35324
Wilczek C, Chayka O, Plachetka A, Klempnauer K.-H.
- 2013. PRMT4 is a novel coactivator of c-Myb-dependent transcription in haematopoietic cell lines. Plos Genetics, 9, e1003343
Streubel G, Bouchard C, Berberich H, Zeller MS, Teichmann S, Adamkiewicz J, Müller R, Klempnauer K-H, Bauer U-M
(See online at https://doi.org/10.1371/journal.pgen.1003343) - 2015. Naphthol AS-E phosphate inhibits the activity of the transcription factor Myb by blocking the interaction with the KIX domain of the coactivator p300. Mol Cancer Ther. 14, 1276-1285
Uttarkar S, Dukare S, Goblirsch M, Jose J, Klempnauer K-H
(See online at https://doi.org/10.1158/1535-7163.MCT-14-0662) - 2016. A conserved patch of hydrophobic amino acids modulates Myb activity by mediating protein-protein interactions. Biochim Biophys Acta. 1859, 914- 921
Dukare S, Klempnauer K-H
(See online at https://doi.org/10.1016/j.bbagrm.2016.04.004) - 2016. Small-Molecule Disruption of the Myb/p300 Cooperation Targets Acute Myeloid Leukemia Cells. Mol Cancer Ther. 15, 2905-2915
Uttarkar S, Piontek T, Dukare S, Schomburg C, Schlenke P, Berdel WE, Müller-Tidow C, Schmidt TJ, Klempnauer K-H
(See online at https://doi.org/10.1158/1535-7163.MCT-16-0185) - 2016. Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction. Blood 127, 1173-1182
Uttarkar S, Dasse E, Coulibaly A, Steinmann S, Jakobs A, Schomburg C, Trentmann A, Jose J, Schlenke P, Berdel WE, Schmidt TJ, Müller-Tidow C, Frampton J, Klempnauer K-H
(See online at https://doi.org/10.1182/blood-2015-09-668632)
