| p53-Induced Apoptosis Occurs in the Absence of p14ARF in Malignant Pleural Mesothelioma1 | |
Abstract/OtherAbstract
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Malignant pleural mesotheliomas (MPMs) are usually wild type for the p53 gene but contain homozygous deletions in the INK4A locus that encodes p14ARF, an inhibitor of p53-MDM2 interaction. Previous findings suggest that lack of p14ARF expression and the presence of SV40 large T antigen (L-Tag) result in p53 inactivation in MPM. We did not detect SV40 L-Tag mRNA in either MPM cell lines or primary cultures, and treatment of p14ARF-deficient cells with cisplatin (CDDP) increased both total and phosphorylated p53 and enhanced p53 DNA-binding activity. On incubation with CDDP, levels of positively regulated p53 transcriptional targets p21WAF, PIG3, MDM2, Bax, and PUMA increased in p14ARF-deficient cells, whereas negatively regulated survivin decreased. Significantly, p53-induced apoptosis was activated by CDDP in p14ARF-deficient cells, and treatment with p53-specific siRNA rendered them more CDDP-resistant. p53 was also activated by: 1) inhibition of MDM2 (using nutlin-3); 2) transient overexpression of p14ARF; and 3) targeting of survivin using antisense oligonucleotides. However, it is noteworthy that only survivin downregulation sensitized cells to CDDP-induced apoptosis. These results suggest that p53 is functional in the absence of p14ARF in MPM and that targeting of the downstream apoptosis inhibitor survivin can sensitize to CDDP-induced apoptosis. |
Authors
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Hopkins-Donaldson, Sally, Belyanskaya, Larisa L, Simões-Wüst, Ana Paula, Sigrist, Brigitte, Kurtz, Stefanie, Zangemeister-Wittke, Uwe, Stahel, Rolf |
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Publisher : Neoplasia Press Inc. Type : Text Format : - |
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Copyright © 2006 Neoplasia Press, Inc. All rights reserved |
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Languages : en |
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