Reprimo, a New Candidate Mediator of the p53-mediated Cell Cycle Arrest at the G2 Phase

Ohki, Rieko; Nemoto, Jiro; Murasawa, Hideki; Oda, Eri; Inazawa, Johji; Tanaka, Nobuyuki; Taniguchi, Tadatsugu

doi:10.1074/jbc.c000235200

Cited by 184 publications

(186 citation statements)

References 38 publications

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“…For example, reprimo is a downstream mediator of p53-induced G2 cell cycle arrest, and its overexpression induces cell cycle arrest at the G2 phase, suggesting that it has tumorsuppressor properties. 60 SPARC is a matricellular glycoprotein involved in diverse biological processes 61 and is frequently silenced by aberrant methylation in pancreatic adenocarcinomas. 23 Several lines of evidence suggest a tumor-suppressor role of SPARC in certain tumor types.…”

Section: Discussionmentioning

confidence: 99%

CpG island methylation profile of pancreatic intraepithelial neoplasia

et al. 2008

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Infiltrating adenocarcinoma of the pancreas is thought to develop through well-defined precursor lesions called pancreatic intraductal neoplasia (PanIN). Despite the exponential growth in our understanding of genetic events that characterize the progression of PanINs to invasive carcinoma, little is known about the role of epigenetic alterations in these precursor lesions. To define the timing and prevalence of methylation abnormalities during early pancreatic carcinogenesis, we investigated the CpG island methylation profile in the various grades of PanINs. Using methylation-specific PCR, we analyzed DNA samples from 65 PanIN lesions for methylation status of eight genes recently identified by microarray approach as aberrantly hypermethylated in invasive pancreatic cancer. Aberrant methylation at any of the eight genes was identified in 68% of all the PanIN lesions examined, and, notably, aberrant methylation was identified in more than 70% of the earliest lesions (PanIN-1A). The average number of methylated loci was 1.1 in PanIN-1A, 0.8 in PanIN-1B, 1.1 in PanIN-2, and 2.9 in PanIN-3 lesions (P ¼ 0.01 for PanIN -3 vs earlier PanINs). Among the genes analyzed, NPTX2 demonstrated an increase in methylation prevalence from PanIN-1 to PanIN-2 (P ¼ 0.0008), and from PanIN-2 to PanIN-3 for SARP2 (P ¼ 0.001), Reprimo (P ¼ 0.01), and LHX1 (P ¼ 0.03). These results suggest that aberrant CpG island hypermethylation begins in early stages of PanINs, and its prevalence progressively increases during neoplastic progression. Keywords: PanIN; pancreatic cancer; methylation specific PCR; DNA methylation Accumulating evidence supports the hypothesis that infiltrating adenocarcinoma of the pancreas develops from noninvasive precursor lesions in the small ducts and ductules, called pancreatic intraductal neoplasia (PanIN). 1,2 Characterization of molecular basis for these precursor lesions may refine our understanding of pancreatic ductal carcinogenesis and also provide important insight into early pancreatic cancer detection strategies and novel targets for chemoprevention. 3 Many of the genetic abnormalities observed in invasive pancreatic cancer have also been observed in PanIN lesions. The reported genetic alterations in PanINs include activating point mutations in the KRAS2 oncogene 4 and inactivation of p16/CDKN2A, 5 TP53, 6 SMAD4/DPC4, 6,7 and BRCA2. 2,8,9 Most of these genetic alterations have been detected in the histologically more advanced PanIN lesions (PanIN-2 and PanIN-3), and the initiating events in neoplastic progression within the pancreatic ducts remains unknown. In addition, telomere shortening is a common genetic abnormality observed in all stages of PanINs including the vast majority of earliest lesions (PanIN-1A). 10 PanIN lesions may be particularly important in patients with a strong family history of pancreatic cancer. [11][12][13] Pancreata in patients with a strong family history of pancreatic cancer are remarkable for the presence of multifocal PanIN lesions, and these PanIN lesions are characteristi...

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Section: Discussionmentioning

confidence: 99%

CpG island methylation profile of pancreatic intraepithelial neoplasia

et al. 2008

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“…Reprimo, a glycosylated, cytoplasmic protein, was identi®ed by using di erential display to ®nd genes induced by ionizing radiation in a p53-dependent manner (Ohki et al, 2000). Saos-2 cells infected with an adenovirus overexpressing Reprimo were arrested with a 4N G2/M content of DNA without condensed chromatin and with Cyclin B in the cytoplasm, suggesting that the cells were in G2 (Ohki et al, 2000).…”

Section: Role Of Reprimo In P53-dependent G2 Arrestmentioning

confidence: 99%

Regulation of the G2/M transition by p53

Taylor¹,

Stark²

2001

Oncogene

1,404

1,110

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“…Reprimo es inducido después de irradiación con rayos X de manera dependiente de p53, causando detención del ciclo celular en fase G2 45 . Adicionalmente, la expresión ectópica de Reprimo también induce la detención G2, en donde se ha observado una inhibición tanto de la actividad de cdc2 como de la translocación nuclear de ciclina-B1.…”

Section: Reprimo Y Cáncer Gástricounclassified

“…Adicionalmente, la expresión ectópica de Reprimo también induce la detención G2, en donde se ha observado una inhibición tanto de la actividad de cdc2 como de la translocación nuclear de ciclina-B1. Estos antecedentes sugieren la participación de Reprimo en la vía de regulación del complejo cdc2/ciclina-B1 45 . Análisis a nivel de ADN indican que RPRM sólo posee un exón de 393 pb, el cual codifica para una proteína de 109 aminoácidos.…”

Section: Reprimo Y Cáncer Gástricounclassified

Bases epigenéticas del cáncer gástrico: oportunidades para la búsqueda de nuevos biomarcadores

2013

Rev. méd. Chile

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Epigenetics in the pathogenesis and early detection of gastric cancerpuc.cl E l cáncer gástrico es la primera causa de muerte por enfermedades neoplásicas en Chile y la segunda en el mundo 1,2 . A pesar de los avances en el tratamiento y una disminución de sus lesiones precursoras 3,4 , recientes publicaciones sugieren un probable aumento de su mortalidad, particularmente en población joven 5 . Estas observaciones, en conjunto con proyecciones de la mortalidad global para los próximos 20 años, sugieren que el cáncer gástrico ocupará la décima causa global de muerte para la década del 2030 6 . El cáncer gástrico se puede clasificar según aspectos clínicos, endoscópicos o histológicos 7-13 . La clasificación más utilizada es la propuesta por Lauren 13 , la cual, según parámetros histológicos, define dos tipos de cáncer gástrico: el intestinal y el difuso. El primero se caracteriza por la formación de estructuras glandulares que semejan la mucosa colónica y que está precedida por una secuencia de lesiones muy bien caracterizadas por Correa y col. 14,15 . Por otra parte, el cáncer gástrico de tipo difuso, no forma estructuras histológicas y en consecuencia no tiene lesiones precursoras reconocidas 16 . Una particularidad importante de la clasificación de Lauren es que ha sido muy útil para estudiar el rol del ambiente, en particular en la variante intestinal 15 . En este sentido, las lesiones precancerosas han demostrado progresar de forma dinámica, desde la gastritis crónica superficial, gastritis crónica atrófica, metaplasia intestinal y finalmente displasia. Estos eventos constituyen las bases del "modelo humano de cáncer gástrico" postulado por Correa 17 . Una de las características fundamentales de este modelo es que junto con identificar una secuencia progresiva de lesiones, señala también la existencia de progresión/regresión de estas lesiones.

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Reprimo, a New Candidate Mediator of the p53-mediated Cell Cycle Arrest at the G2 Phase

Cited by 184 publications

References 38 publications

CpG island methylation profile of pancreatic intraepithelial neoplasia

CpG island methylation profile of pancreatic intraepithelial neoplasia

Regulation of the G2/M transition by p53

Bases epigenéticas del cáncer gástrico: oportunidades para la búsqueda de nuevos biomarcadores

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