Molecular mechanisms of p53 target gene preference

• Applicant: Professor Dr. Stephan Singer
• Subject Area: Pathology
• Term: from 2008 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 82675559

The p53 tumor suppressor protein plays a pivotal role in the prevention of human cancer. In response to various types of stress p53-dependent expression of distinct subsets of target genes induces cell cycle arrest, senescence, or apoptotic cell death. However, the underlying molecular mechanisms that dictate p53 target gene preference and thereby determining the nature of the cellular response are poorly defined. Using a novel ChIP/proteomic approach Prives and co-workers recently identified the human cellular apoptosis susceptibility protein (hCAS) to co-activate a subset of p53 target promoters and to modulate histone methylation. Furthermore, preliminary data indicate that this hCAS/p53 containing transcriptional complex is related to the nuclear periphery. Therefore, the project aims to analyze the molecular mechanisms by which the hCAS/p53 multiproteincomplex regulates transcription depending on the subnuclear localization of its target gene promoters. Furthermore, overexpression of hCAS (e.g. in hepatocellular carcinoma) implicates p53-independent oncogenic properties that will also be analyzed. The comprehensive analysis of p53/hCAS-mediated regulation of transcription will give new insights in the molecular basis of the p53 target gene preference and may provide a new determinant of the p53 response.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Carol L. Prives