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Projekt
The role of actin nucleators and nucleation promoting factors in nuclear gene expression via MRTF
Antragsteller
Professor Dr. Guido Posern
Fachliche Zuordnung
Zellbiologie
Förderung
Förderung von 2010 bis 2018
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 170443560
Beside its prominent role in cytoplasmic F-actin formation, actin nucleation also affects processes within the cell nucleus, such as gene expression through SRF and its coactivator MAL/MRTF. However, the precise connection between the nucleation promoting factors (NPFs), nuclear actin and MAL/SRF is unclear. The aim of this proposal is to elucidate the role of WH2-domains and -NPFs in nuclear processes, i.e. MAL/SRF-mediated transcription and formation of nuclear actin polymers. Previous work demonstrated that MAL is activated by its release from a repressive G-actin complex. NPFs often contain G-actin binding WH2 domains. Preliminary results and structural data are consistent with our working hypothesis that WH2 domains displace MAL from G-actin and thereby activate SRF-mediated transcription; we will test this directly in cellular assays. Further, we will analyse the WH2-MAL competition by biochemical experiments and in living cells by imaging. Using both candidate approaches and unbiased screening, we will attempt to identify the critical WH2-containing NPFs. Moreover, we will determine whether they are nuclear, affect nuclear MAL:actin complexes, and nuclear actin polymerisation. We expect to characterise a new function of NPFs in transcription, resolve the mechanism underlying MAL:actin dissociation, and to shed light on nuclear actin assembly.
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