Journal Article

Gene expression profile in a glioma cell line resistant to cell death induced by a the chimeric tumor suppressor-1 (CTS-1), a dominant-positive variant of p53—the role of NFκB

Janina Seznec, Simone Weit and Ulrike Naumann

in Carcinogenesis

Volume 31, issue 3, pages 411-418
Published in print March 2010 | ISSN: 0143-3334
Published online December 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp319
Gene expression profile in a glioma cell line resistant to cell death induced by a the chimeric tumor suppressor-1 (CTS-1), a dominant-positive variant of p53—the role of NFκB

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The identification of genes involved in carcinogenesis and tumor progression is of great interest since these genes might be feasible as candidates for new tumor-targeted therapy strategies. Chimeric tumor suppressor-1 (CTS-1), an artificial synthetic variant of p53, resists common p53 inactivation and could therefore be defined as a dominant-positive p53 variant. Overexpression of CTS-1 induces caspase-independent cell death. We used whole-genome microarray expression analysis in a parental (229P) and a CTS-1-resistant glioma cell line (229Res) to analyze alterations in gene expression in Ad-CTS-1-infected and in uninfected parental and resistant cells. In total, 700 genes were differentially expressed in infected and 313 genes in uninfected 229Res versus 229P cells. Ingenuity Pathway Analysis determined a variety of differentially expressed genes in Ad-CTS-1-infected cells that were members of intracellular networks with central tumor-involved players such as nuclear factor-kappaB (NFκB), protein kinase B/AKT or transforming growth factor-β. Here we focused on the function of NFκB in Ad-CTS-1-mediated cell death in glioma. NFκB was activated in Ad-CTS-1-infected 229P but not 229Res cells. NFκB activation was accompanied by the induction of cell death in parental cells. Inhibition of NFκB activity by expression of an IκB super repressor or upregulation of the NFκB-linked gene Bex protected parental cells to Ad-CTS-1-induced cell death, whereas knockdown of Bex sensitized both parental and resistant cells. Taken together, these data suggest that activation of the normally antiapoptotic protein NFκB does not always necessarily protect cells from apoptosis but, in the glioma cell lines tested so far, and in an environment where p53 is constitutively active, also leads to the induction of cell death.

Journal Article.  5564 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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