RESUMEN
p57(KIP2) is an imprinted gene located at the chromosomal locus 11p15.5. It is a cyclin-dependent kinase inhibitor belonging to the CIP/KIP family, which includes additionally p21(CIP1/WAF1) and p27(KIP1). It is the least studied CIP/KIP member and has a unique role in embryogenesis. p57(KIP2) regulates the cell cycle, although novel functions have been attributed to this protein including cytoskeletal organization. Molecular analysis of animal models and patients with Beckwith-Wiedemann Syndrome have shown its nodal implication in the pathogenesis of this syndrome. p57(KIP2) is frequently down-regulated in many common human malignancies through several mechanisms, denoting its anti-oncogenic function. This review is a thorough analysis of data available on p57(KIP2), in relation to p21(CIP1/WAF1) and p27(KIP1), on gene and protein structure, its transcriptional and translational regulation, and its role in human physiology and pathology, focusing on cancer development.
Asunto(s)
Ciclo Celular , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Animales , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/química , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/genética , Neoplasias/patología , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Osteosarcoma is the most common primary bone cancer. Mutations of the RB gene represent the most frequent molecular defect in this malignancy. A major consequence of this alteration is that the activity of the key cell cycle regulator E2F1 is unleashed from the inhibitory effects of pRb. Studies in animal models and in human cancers have shown that deregulated E2F1 overexpression possesses either "oncogenic" or "oncosuppressor" properties, depending on the cellular context. To address this issue in osteosarcomas, we examined the status of E2F1 relative to cell proliferation and apoptosis in a clinical setting of human primary osteosarcomas and in E2F1-inducible osteosarcoma cell line models that are wild-type and deficient for p53. Collectively, our data demonstrated that high E2F1 levels exerted a growth-suppressing effect that relied on the integrity of the DNA damage response network. Surprisingly, induction of p73, an established E2F1 target, was also DNA damage response-dependent. Furthermore, a global proteome analysis associated with bioinformatics revealed novel E2F1-regulated genes and potential E2F1-driven signaling networks that could provide useful targets in challenging this aggressive neoplasm by innovative therapies.
Asunto(s)
Neoplasias Óseas/metabolismo , Factor de Transcripción E2F1/metabolismo , Regulación Neoplásica de la Expresión Génica , Osteosarcoma/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/fisiología , Western Blotting , Neoplasias Óseas/genética , Línea Celular Tumoral , Proliferación Celular , Niño , Daño del ADN , Reparación del ADN , Proteínas de Unión al ADN/metabolismo , Factor de Transcripción E2F1/genética , Electroforesis en Gel Bidimensional , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Masculino , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , Osteosarcoma/genética , Proteína Tumoral p73 , Proteína p53 Supresora de Tumor/deficiencia , Proteínas Supresoras de Tumor/metabolismo , Adulto JovenRESUMEN
Knowing the status of molecules involved in cell cycle control in cancer is vital for therapeutic approaches aiming at their restoration. The p27(KIP1) and p57(KIP2) cyclin-dependent kinase inhibitors are nodal factors controlling normal cell cycle. Their expression in normal lung raises the question whether they have a mutual exclusive or redundant role in nonsmall cell lung cancer (NSCLC). A comparative comprehensive analysis was performed in a series of 70 NSCLCs. The majority of cases showed significantly reduced expression of both members compared to normal counterparts. Low KIP protein levels correlated with increased proliferation, which seems to be histological subtype preponderant. At mechanistic level, degradation by SKP2 was demonstrated, in vivo and in vitro, by siRNA-methodology, to be the most important downregulating mechanism of both KIPs in NSCLC. Decreased p57(KIP) (2)-transcription complements the above procedure in lowering p57(KIP2)-protein levels. Methylation was the main cause of decreased p57(KIP) (2)-mRNA levels. Allelic loss and imprinting from LIT1 mRNA contribute also to decreased p57(KIP2) transcription. In vitro recapitulation of the in vivo findings, in A549 lung cells (INK4A-B((-/-))), suggested that inhibition of the SKP2-degradation mechanism restores p27(KIP1) and p57(KIP2) expression. Double siRNA treatments demonstrated that each KIP is independently capable of restraining cell growth. An additional demethylation step is required for complete reconstitution of p57(KIP2) expression in NSCLC.