Role of AIM2, a selected target gene of microsatellite instability, in the pathogenesis of DNA mismatch repair-deficient colon cancers
Zusammenfassung der Projektergebnisse
The major goal of this research project was to elucidate the biologic function and pathogenic impact of AIM2 on MSI colon tumorigenesis. The data and results obtained from this study demonstrate that: I. Lack of AIM2 induction in some MSI CRC cell lines is not caused by a general defect of the IFN pathway. We would like to emphasize that the generation of AIM2 expressing clones required a more labor, time, and resources than initially anticipated. Once generated, these clones showed severely impaired growth and viability features thus extending and delaying all subsequent studies. Accordingly, we had to cut down on the experimental program and hence skipped the proposed AIM2 expression studies in human tissues by tn Situ Hybridization (Ad Id). II. Restoration of AIM2 expression in AIM2 deficient HCT116 cells suppressed grovrth, reduced viability, increased fibronectin-induced spreading and caused upregulation of several genes encoding immunomodulators as well as components of cell /extracellular matrix interactions. However, a constitutive low level of Aim2 expression does not confer lethality. III. AIM2wt and AIM2-1 both inhibit endogenous (unstimulated) and TNF-a-stimulated NF-kB signaling activity in a colorectal cancer cell line but not in embryonic 293T cells suggesting a cell type specific mechanism that may depend on the basic endogenous NF-kB activity IV. Heterodimerization studies of wt/wt and wt/mut AIM2 required construction of differently tagged vA and (-1) AIM2 proteins which we have accomplished by generating EGFP- AIM2 and FLAG-AIM2 fusion proteins. Instead of pursuing the functional consequences of heterodimer and homodimer activities we decided to include the AIM2(-1) mutant clones in our studies of AIM2 localization and NFk B transcriptional activity (Ad III). In all these assays no difference between wt and mutant AIM2 could be identified.
Projektbezogene Publikationen (Auswahl)
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"The role of Absent in Melanoma 2 (AIM2) in DNA Mismatch repair-deficient colon carcinomas" 2nd Biennial Scientific Meeting of the International Society for Gastrointestinal Hereditary Tumours (InSiGHT); Yokohama, Japan, March 2007
Susanne Dihimann
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2007. The putative tumor suppressor AIM2 is frequently affected by different genetic alterations in microsatellite unstable colon cancers. Genes Chromosomes Cancer Dec; 46(12):1080-9
Woemer, SM, Kloor, M, Schwitalte, Y, Youmans, H, von Knebel Doeberitz, M, Gebert, J. and Dihimann, S
