Die Regulation des Tumorsuppressors p53 durch den neuen INHAT-Repressor NIR
Final Report Abstract
Our work has identified NIR (novel INHAT (inhibitor of histone acetyltransferases) repressor)) as a new, non-DNA-binding negative regulator of gene transcription that is bound and recruited to promoters by transcription factors of the p53 family of tumour suppressors and developmental regulators, as well as by Murine Double Minute 2 (MDM2), itself an important non-DNA-binding negative regulator of the p53 family. NIR is the only known INHAT harbouring two rather than just one INHAT domains. It is a nucleolar-nucleoplasmic shuttle protein which is regulated by phosphorylation to be predominantly nucleolar in G1/S phase of the cell cycle and mostly nucleoplasmic in G2/M. In the nucleolus, NIR may exert functions in rRNA processing and ribosome biogenesis. In the nucleoplasm at promoters, NIR acts as a repressor of gene transactivation by inhibiting the coactivating histone acetyltransferases p300/CBP which acetylates histones in order to open up chromatin and which acetylates p53 in order to support its binding to DNA and its sustained dissociation from the negative regulator MDM2. Thus, by binding to p53 and MDM2 in a ternary complex, NIR may stabilize the MDM2-p53 complex and help MDM2 to suppress p53 as a transcriptional activator. Acute Myeloid Leukemias (AMLs) can be subdivided, according to the expression levels of NIR, into ‘NIR-low’ and ‘NIR-high’ tumours. The expression levels correlated with defined chromosomal aberrations and specific gene expression profiles but failed to correlate with the overall survival of the patients. Future work may focus on the dissection and more detailed investigation of NIR’s nucleolar vs. nucleoplasmic functions, and on NIR’s role in the development of the skin in transgenic mice.
Publications
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2010. NIR, an inhibitor of histone acetyltransferases, regulates transcription factor TAp63 and is controlled by the cell cycle. Nucl. Acids. Res. 38(10): 3159-71
Heyne, K., V. Willnecker, J. Schneider, M. Conrad, N. Raulf, R. Schüle, K. Roemer
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2014. Transcriptional repressor NIR interacts with the p53-inhibiting ubiquitin ligase MDM2. Nucl. Acids Res. 42(6): 3565- 79
Heyne, K., J. Förster, R. Schüle, Roemer K.
