p53-induced apoptosis occurs in the absence of p14(ARF) in malignant pleural mesothelioma.
Neoplasia
; 8(7): 551-9, 2006 Jul.
Article
en En
| MEDLINE
| ID: mdl-16867217
ABSTRACT
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Neoplasias Pleurales
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Regulación Neoplásica de la Expresión Génica
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Genes p53
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Proteína p53 Supresora de Tumor
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Apoptosis
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Proteína p14ARF Supresora de Tumor
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Mesotelioma
Límite:
Humans
Idioma:
En
Revista:
Neoplasia
Asunto de la revista:
NEOPLASIAS
Año:
2006
Tipo del documento:
Article
País de afiliación:
Suiza