Medizinische Universität Graz - Research portal
Selected Publication:
Bramerdorfer, G.
Dissecting the intricate role of disordered regions in FOXO4-p53 interaction and the phase separation of FOXO4 and p53 in vitro.
[ Diplomarbeit/Master Thesis (UNI) ] Universität Graz; 2023.
FullText
- Authors Med Uni Graz:
- Advisor:
- Madl Tobias
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- Abstract:
- P53 and the class of Forkhead Box O (FOXO) proteins are important transcription factors (TF) with impact on the cell cycle, cell metabolism and human health. As p53 is an important tumor suppressor and cellular regulator, and FOXOs play an important role in intracellular signaling pathways which are related to senescence, cell cycle control and growth, the investigation on these interacting binding partners can help to get a better understanding of the role of FOXO4-p53 axis in particularly cancer and aging. FOXOs are shown to bind to the DNA binding domain of p53 (DBD) via their intrinsically disordered region, called conserved region 3 (CR3), and therefore are believed to have an influence on the way p53 regulates genes. Vice versa, the disordered transactivation domain (TAD) of p53 shows binding to the DNA binding domain of FOXO4, called Forkhead domain (FH). Insights in the FOXO4-p53 axis have identified their interaction playing a critical role in maintaining the viability of senescent cells. Recent research in the group of Peter de Keizer in cooperation with AG Madl further shows that the inhibition of the interaction of FOXO4 and p53 has beneficial effects on aging of mice. The researchers designed a short peptide, which is shown to inhibit the binding of p53 and FOXO4 by direct interaction with p53 DBD and triggers increased fur density and improved renal function in aged mice. The peptide mediates the release of active p53 from promyelocytic leukaemia bodies (PML-bodies) at DNA-segments with chromatin alteration reinforcing senescence (DNA-SCARS) and cause senescent sell specific apoptosis in IMR90 fibroblasts (...)