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Artículo

Isoprenylcysteine carboxy methyltransferase (ICMT) is associated with tumor aggressiveness and its expression is controlled by the p53 tumor suppressor

Borini Etichetti, Carla MariaIcon ; Di Benedetto, CarolinaIcon ; Rossi, Carolina; Baglioni, María VirginiaIcon ; Bicciato, Silvio; Del Sal, Giannino; Menacho Márquez, Mauricio ArielIcon ; Girardini Brovelli, Javier EnriqueIcon
Fecha de publicación: 03/2019
Editorial: American Society for Biochemistry and Molecular Biology
Revista: Journal of Biological Chemistry
ISSN: 0021-9258
e-ISSN: 1083-351X
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Bioquímica y Biología Molecular

Resumen

Isoprenyl cysteine carboxyl methyltransferase (ICMT) plays a key role in post-translational regulation of prenylated proteins. On the basis of previous results, we hypothesized that the p53 pathway and ICMT expression may be linked in cancer cells. Here, we studied whether WT p53 and cancer-associated p53 point mutants regulate ICMT levels and whether ICMT overexpression affects tumor progression. Studying the effect of p53 variants on ICMT mRNA and protein levels in cancer cells, we found that WT p53 and p53 mutants differentially affect ICMT expression, indicating that p53 status influences ICMT levels in tumors. To investigate the underlying mechanisms, we constructed ICMT?luciferase reporters and found that WT p53 represses ICMT transcription. In contrast, p53 mutants showed a positive effect on ICMT expression. Promoter truncation analyses pinpointed the repressive effect of WT p53 to the 209 and 14 region on the ICMT promoter, and ChIP assays indicated that WT p53 is recruited to this region. Instead, a different promoter region was identified as responsible for the mutant p53 effect. Studying the effect of ICMT overexpression on tumor-associated phenotypes in vitro and in vivo, and analyzing breast and lung cancer databases, we identified a correlation between p53 status and ICMT expression in breast and lung cancers. Moreover, we observed that ICMT overexpression is correlated with negative clinical outcomes. Our work unveils a link between postprenylation protein processing and the p53 pathway, indicating that the functional interplay between WT and mutant p53 alters ICMT levels, thereby affecting tumor aggressiveness.
Palabras clave: PROTEIN PRENILATION , CARBOXYMETHYLATION , ICMT , MUTANT P53 , CANCER
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution 2.5 Unported (CC BY 2.5)
Identificadores
URI: http://hdl.handle.net/11336/153062
URL: http://www.jbc.org/lookup/doi/10.1074/jbc.RA118.006037
DOI: https://doi.org/10.1074/jbc.RA118.006037
Colecciones
Articulos (IIDEFAR)
Articulos de INSTITUTO DE INVESTIGACIONES PARA EL DESCUBRIMIENTO DE FARMACOS DE ROSARIO
Articulos(CCT - ROSARIO)
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - ROSARIO
Articulos(IBR)
Articulos de INST.DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
Articulos(IDICER)
Articulos de INSTITUTO DE INMUNOLOGIA CLINICA Y EXPERIMENTAL DE ROSARIO
Citación
Borini Etichetti, Carla Maria; Di Benedetto, Carolina; Rossi, Carolina; Baglioni, María Virginia; Bicciato, Silvio; et al.; Isoprenylcysteine carboxy methyltransferase (ICMT) is associated with tumor aggressiveness and its expression is controlled by the p53 tumor suppressor; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry; 294; 13; 3-2019; 5060-5073
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