Objetivo The tumour suppressor p53 is the most frequently mutated gene in human cancer. It is involved in a large number of cellular responses upon stress-signals leading to growth arrest, apoptosis, DNA-repair senescence or differentiation. Although many target-genes have been described, it is still unresolved how the different choices of target-genes and the subsequent cellular responses are brought about. Furthermore, while a large number of p53-target genes for transcriptional activation were identified, its sequence-specific transcriptional repression function is not as well documented. The here proposed research plan would contribute to our understanding of how these choices between transcriptionally activated and repressed genes are made in viva upon specific stress-signals. To this end the selective assembly of gene and stress-specific p53-coactivator and co repressor complexes will be studied in vivo as well as the genomic environment of the various transcriptional responses.Furthermore, the p53-transcriptional repression function will be analysed, identifying the general mechanism of p53-transrepression as well as bona fide repressed target-genes and their biological function. Finally, the regulatory mechanisms of the choice of target-genes and of the transcriptional complex assembly will be studied in a cellular environment elucidating the specific processes that ultimately lead to a distinct stress-response in a cell. In order to study the molecular basis of p53's transcriptional activation and repression function it will be of enormous importance to perform this work in an environment that is internationally known for its work and expertise on transcription.The practical and theoretical support of a basic transcription laboratory will allow the applicant to be competitive in the p53-field. In terms of her practical work, the applicant chose Prof Dr. Henk Stunnenberg's department as one of the first European laboratories that routinely and successfully performs Chromatin-Immune precipitations from various cell-systems and with a broad spectrum of antibodies. Since Chromatin-Immune precipitations are the cornerstones of the applicant's proposed research of in vivo analysis of p53's transcriptional activation and repression function, the choice of the host-laboratory was crucial in this respect. The host institute will benefit from the applicant's broad knowledge in molecular and cellular techniques, e.g. her expertise in immuno-fluorescence which she will be continuing to use also in the new host laboratory. Ámbito científico medical and health sciencesclinical medicineoncology Programa(s) FP5-HUMAN POTENTIAL - Programme for research, technological development and demonstration on "Improving the human research potential and the socio-economic knowledge base" (1998-2002) Tema(s) Data not available Convocatoria de propuestas Data not available Régimen de financiación RGI - Research grants (individual fellowships) Coordinador STICHTING KATHOLIEKE UNIVERSITEIT Aportación de la UE Sin datos Dirección Geert Grootepelin 26 zuid 6500 HB NIJMEGEN Países Bajos Ver en el mapa Coste total Sin datos
