Rolle der p300-abhängigen Proteinacetylierung in der Entwicklung und Tumorsuppression | |
| Kennziffer | 20.126.87p |
| Projektleiter/in | PD Dr. Werner Lutz |
| Schlagwörter |
Histonacetylierung B-Zell-Differenzierung Histondeacetylase-Inhibitoren Autoimmunität Selbsttoleranz |
| Kurzbeschreibung |
Acetylation has in recent years emerged as a protein modification matching phosphorylation in versatility and importance. p300 and the closely related CBP were among the first vertebrate proteins to be recognized as acetyltransferases (Bannister and Kouzarides, 1996). p300/CBP homologous proteins have been found in all multicellular organisms analyzed so far including plants but are missing in yeast (Bordoli et al., 2001). p300 is best known for its role as a transcriptional co-regulator of a huge number of transcription factors. Among the substrates of p300 acetyltransferase activity are histones and the very same transcription factors that recruit p300 as a co-regulator. Thus, via acetylation p300 can modulate both the activity of transcription factors and the chromatin status of their target genes. Not unexpected for a highly polygamous protein p300 has been implicated in virtually every aspect of an organisms life ranging from circadian rhythm (Etchegaray et al., 2003) and differentiation (Blobel, 2000) to DNA-repair (Hasan et al., 2001). Indeed, p300-deficient mice die at day E9.5 of embryonic development (Yao et al., 1998). To specifically analyze the biological function of the acetyltransferase activity of p300 we have created knockin mice with a point mutation in the acetyltransferase domain of p300. The protein encoded by the mutant allele p300AS is full length but has no detectable acetyltransferase activity. Mice that express a single allele of p300AS - in contrast to mice heterozygous for a null allele of p300 - die during embryogenesis or at birth indicating that p300AS is a dominant-negative allele (Shikama et al., 2003). The mice show defects in several organ systems including heart, lung and muscle. A detailed analysis of muscle differentiation using mutant mice and embryonic stem cells homozygous for p300AS suggests that these defects are the result of impaired differentiation (Roth et al., 2003). p300AS is not only a dominant negative but also a conditional allele, because it is only expressed after Cre-recombinase mediated removal of the neo gene from one of its introns. Thus, p300AS mice offer the unique opportunity to identify processes that require the acetyltransferase activity of p300 in a particular tissue in vivo. We use this experimental system to address the role of p300-dependent protein acetylation in tumor suppression and autoimmune disease.
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| Laufzeit | 01.01.2002 - 31.12.2010 |
| Finanzierung | DFG |
| Zugehörigkeit | Transcriptional control in developmental processes Internationales Graduiertenkolleg Universität Marburg, Universität Gießen, Universität Rotterdam (DFG-GRK 767) |
| Publikationen |
Bordoli, L., Netsch, M., Luthi, U., Lutz, W., and Eckner, R. (2001). Plant orthologs of p300/CBP: conservation of a core domain in metazoan p300/CBP acetyltransferase-related proteins. Nucleic Acids Res 29, 589-597. Roth, J. F., Shikama, N., Henzen, C., Desbaillets, I., Lutz, W., Marino, S., Wittwer, J., Schorle, H., Gassmann, M., and Eckner, R. (2003). Differential role of p300 and CBP acetyltransferase during myogenesis: p300 acts upstream of MyoD and Myf5. Embo J 22, 5186-5196. Shikama, N.*, Lutz, W.*, Kretzschmar, R., Sauter, N., Roth, J. F., Marino, S., Wittwer, J., Scheidweiler, A., and Eckner, R. (2003). Essential function of p300 acetyltransferase activity in heart, lung and small intestine formation. Embo J 22, 5175-5185. *Noriko Shikama and Werner Lutz contributed equally to this work.
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