p53-induced apoptosis occurs in the absence of p14(ARF) in malignant pleural mesothelioma

Hopkins-Donaldson, Sally; Belyanskaya, Larisa L; Simões-Wüst, Ana Paula; Sigrist, Brigitte; Kurtz, Stefanie; Zangemeister-Wittke, Uwe; Stahel, Rolf (2006). p53-induced apoptosis occurs in the absence of p14(ARF) in malignant pleural mesothelioma. Neoplasia, 8(7), pp. 551-9. New York, N.Y.: Nature America 10.1593/neo.06148

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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 p14(ARF), an inhibitor of p53-MDM2 interaction. Previous findings suggest that lack of p14(ARF) 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 p14(ARF)-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 p21(WAF), PIG3, MDM2, Bax, and PUMA increased in p14(ARF)-deficient cells, whereas negatively regulated survivin decreased. Significantly, p53-induced apoptosis was activated by CDDP in p14(ARF)-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 p14(ARF); 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 p14(ARF) in MPM and that targeting of the downstream apoptosis inhibitor survivin can sensitize to CDDP-induced apoptosis.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Zangemeister-Wittke, Uwe

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1522-8002

ISBN:

16867217

Publisher:

Nature America

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:48

Last Modified:

18 Feb 2016 14:32

Publisher DOI:

10.1593/neo.06148

PubMed ID:

16867217

Web of Science ID:

000239283200003

URI:

https://boris.unibe.ch/id/eprint/20241 (FactScience: 3428)

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