Research Report 2010 - MDC

Structure of the GroupPeter DanielGroup LeaderProf. Dr. Peter DanielScientistsDr. Bernhard GillissenDr. Philipp HemmatiDr. Christian ScholzDr. Isrid SturmDr. Jana WendtGraduate StudentsCindrilla ChumduriMonika DejewskaNina GebhardtClinical and Molecular OncologyVirtually all medical anticancer therapies rely on the induction of cell cycle arrest or celldeath in the malignant cells. Consequently, the analysis of such genetic events allows forthe identification of patients at risk for an insufficient response to treatment and poorsurvival. Such analyses therefore provide a rational basis for a molecular understanding of theresponse to anticancer therapies and the clinical use of cancer therapeutics. The aim of thegroup is, therefore, to define genetic defects in cancer that result in aggressive disease, poorprognosis, and resistance to clinical cancer therapy. To this end, we have established anextensive genotyping and functional genomics program in solid tumors and leukemias. Recentdata indicate that specific defects in cellualr stress pathways leading to cellular resistancemay be overcome by rationally selected targeted anticancer drugs. In addition, these systemsare exploited to gain insights into novel aspects of cell cycle and cell death regulation andtheir intricate interactions.Understanding resistance to anticancer therapyMany anticancer therapies activate nuclear stressresponses to induce cell cycle arrest and DNA repair.When repair fails, the same stress responses trigger cellularsenescence or death and demise of the affectedcell. The molecular basis of these events has been studiedextensively during recent years and comprehensivemodels are now established for large parts of these signalingevents. We have investigated the consequencesof genetic defects in genes acting as effectors or inducersof p53 that trigger apoptosis and cell cycle arrestprograms upon genotoxic stress. In this context, werecently described selective loss of multiple BH3-onlyproteins, pro-apoptotic homologs of the Bcl-2 family,including Nbk and Bim in renal carcinoma. This is a unifyingfeature of renal carcinoma and appears to belinked to the impressive clinical resistance of this tumorentity to anticancer therapy.Regulation of cell death by pro-apoptotic Bcl-2family membersApoptosis is mediated through at least three majorpathways that are regulated by (1) the death receptors,(2) the mitochondria, and (3) the endoplasmic reticulum(ER). In most cells, these pathways are controlled bythe Bcl-2 family of proteins that can be divided intoantiapoptotic and proapoptotic members. Althoughthe overall amino acid sequence homology betweenthe family members is relatively low, they contain highlyconserved domains, referred to as Bcl-2 homologydomains (BH1 to BH4) that are essential for homo- andheterocomplex formation as well as for their cell deathinducing capacity. Structural and functional analysesrevealed that the proapoptotic homologs can be subdividedinto the Bax subfamily and the growing BH3-onlysubfamily. BH3-only proteins link upstream signalsfrom different cellular or functional compartments tothe mitochondrial apoptosis pathway (see figure).Puma, Noxa, Hrk, and Nbk (Bik) are induced by p53 andmediate cell death originating from the nucleus, e.g.upon DNA damage. Nbk localizes to the ER and activatesBax (but not Bak) indirectly, through a ER-initiateddeath pathway that has been recently elucidated by ourgroup.The aim of our work is to gain structural and functionalinsights into how these subfamilies promote orinhibit cell death signals and how these properties maybe utilized for development of apoptosis-promoting132 Cancer Research