STAT1 represses Skp2 gene transcription to promote p27Kip1 stabilization in Ras-transformed cells.

Wang, Shuo; Raven, Jennifer F; Koromilas, Antonis E

Wang, Shuo; Raven, Jennifer F; Koromilas, Antonis E.

Afiliación

Wang S; Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Room 508, 3999 Cote Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2. swang@ldi.jgh.mcgill.ca

Mol Cancer Res ; 8(5): 798-805, 2010 May.

Article en En | MEDLINE | ID: mdl-20407011

RESUMEN

The S-phase kinase-associated protein 2 (Skp2) is an F-box protein that serves as a subunit of the Skp1-Cullin-F-box ubiquitin protein ligase complex. Skp2 is overexpressed in many tumors and promotes tumor formation through its ability to induce the degradation of proteins with antiproliferative and tumor-suppressor functions, such as p27(Kip1). The signal transducer and activator of transcription 1 (STAT1) is a key regulator of the immune system through its capacity to act downstream of interferons. STAT1 exhibits tumor-suppressor properties by inhibiting oncogenic pathways and promoting tumor immunosurveillance. Previous work established the antitumor function of STAT1 in Ras-transformed cells through the induction of p27(Kip1) at the transcriptional level. Herein, we unveil a novel pathway used by STAT1 to upregulate p27(Kip1). Specifically, we show that STAT1 impedes Skp2 gene transcription by binding to Skp2 promoter DNA in vitro and in vivo. Decreased Skp2 expression by STAT1 is accompanied by the increased stability of p27(Kip1) in Ras-transformed cells. We further show that impaired expression of STAT1 in human colon cancer cells containing an activated form of K-Ras is associated with the upregulation of Skp2 and downregulation of p27(Kip1). Our study identifies Skp2 as a new target gene of STAT1 in Ras-transformed cells with profound implications in cell transformation and tumorigenesis.

Asunto(s)

Transformación Celular Neoplásica/genética; Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo; Proteínas Quinasas Asociadas a Fase-S/genética; Factor de Transcripción STAT1/fisiología; Animales; Línea Celular Transformada; Línea Celular Tumoral; Transformación Celular Neoplásica/metabolismo; Regulación hacia Abajo/genética; Regulación Neoplásica de la Expresión Génica/genética; Células HCT116; Humanos; Ratones; Ratones Noqueados; Regiones Promotoras Genéticas/genética; Estabilidad del ARN/genética; Proteínas Represoras/fisiología; Proteínas Quinasas Asociadas a Fase-S/antagonistas & inhibidores; Factor de Transcripción STAT1/genética; Regulación hacia Arriba/genética; Proteínas ras/genética; Proteínas ras/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transformación Celular Neoplásica / Proteínas Quinasas Asociadas a Fase-S / Factor de Transcripción STAT1 / Inhibidor p27 de las Quinasas Dependientes de la Ciclina Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Mol Cancer Res Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2010 Tipo del documento: Article Pais de publicación: Estados Unidos

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