Death receptors and death ligands

The transcription factor p53, also named „guardian oft the genome“, is mutated and therefore inactivated in nearly 50 % of all tumors. Loss of p53-activity is an essential step during tumor development and, tumor progression. Inactivating p53-mutations play an important role in the development of resistance against chemo- and radiationtherapy in many tumor species, including malignant glioma. Restoration of p53 activity might therefore be a promising strategy to overcome this resistance. The chimeric tumor suppressor (CTS)-1 is a synthetic p53 analog, based on the sequence and structure of p53. In contrast to p53, CTS-1 could not be inactivated due to MDM2-mediated proteasomal degradation. In consequence of this, CTS-1 could also be entitled dominant-positive p53. Overexpression of CTS-1, but not of p53, induces cell death in glioma cells. To identify and to characterize cell-death-inducing genes and therefore to identify novel putative target genes for a glioma-specific gene therapy, we generated a CTS-1-resistant glioma cell line. Whole-Genome-Microarray-expression analysis leads to the identification of approximately 1000 genes differentially regulated in resistant versus parental cells. Analysis concerning the function of these differentially expressed genes demonstrated that these genes are involved in cancer-relevant processes such as tumor cell migration, invasion, and in processes regulating cell cycle progression as well as apoptosis. A long-term objective of this project will be the identification and characterization of therapy-relevant target genes for a future anti-glioma gene therapy.

Supported by the: Germany Research Council

(Contact person: Dr. U. Naumann)