RESUMEN
Von Hippel-Lindau (VHL) syndrome is characterized by hemangioblastomas of the brain, spinal cord, and retina, renal cysts, clear cell renal cell carcinoma, and pheochromocytoma. VHL is caused by mutations in the VHL tumor suppressor gene. We attempted to detect mutation in the VHL gene in a 5-generation Chinese family with VHL. We identified a novel small duplication that altered the reading frame downstream and created a premature TGA stop signal, resulting in severely truncated pVHL30 (p.Gly114Serfs*50) and pVHL19 (p.Gly61Serfs*50). This change was predicted to be an elongin-binding domain deletion.
Asunto(s)
Pueblo Asiatico/genética , Codón sin Sentido , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , China , Femenino , Mutación del Sistema de Lectura , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Linaje , Adulto JovenRESUMEN
BACKGROUND: Our previous study revealed that proline-rich tyrosine kinase 2 (Pyk2) is implicated in both anchorage-independent growth and anoikis resistance in lung cancer cells. This study aims to explore the expression and clinical significance of Pyk2 and its phosphorylated forms in non-small-cell lung cancer (NSCLC). METHODS: The mRNA and protein levels of Pyk2 or cancer stem cell markers (ALDH1a1, ABCG2 and Bmi-1) were either examined by reverse transcription-PCR or western blotting. An immunohistochemistry (IHC) assay was conducted to analyse the expression of Pyk2 and its phosphorylated forms in 128 NSCLC cases. RESULTS: The levels of Pyk2 mRNA, total protein, and its phosphorylated form pY881 were higher in lung cancer lesions than in the paired noncancerous tissues. The IHC analysis showed the levels of the Pyk2 and Pyk2[pY881] proteins were highly expressed in 70 (54.7%) and 77 (60.2%) cases, respectively. Both Pyk2 and Pyk2[pY881] were independent prognostic factors for NSCLC patients. The gain and loss study of Pyk2 function revealed that Pyk2 could upregulate the expression of ALDH1a1, ABCG2 and Bmi-1 and enhance the ability of colony formation in soft agar assay in A549 and H460 cells. CONCLUSION: Both Pyk2 and phosphorylated Pyk2[pY881] are potential prognostic factors and therapeutic targets for NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , TYK2 Quinasa/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/biosíntesis , Transportadoras de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Aldehído Deshidrogenasa/biosíntesis , Aldehído Deshidrogenasa/genética , Familia de Aldehído Deshidrogenasa 1 , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Fosforilación , Complejo Represivo Polycomb 1/biosíntesis , Complejo Represivo Polycomb 1/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Retinal-Deshidrogenasa , TYK2 Quinasa/genética , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
The receptor tyrosine kinase (RTK) signaling pathway is used reiteratively during the development of all multicellular organisms. While the core RTK/Ras/MAPK signaling cassette has been studied extensively, little is known about the nature of the downstream targets of the pathway or how these effectors regulate the specificity of cellular responses. Drosophila yan is one of a few downstream components identified to date, functioning as an antagonist of the RTK/Ras/MAPK pathway. Previously, we have shown that ectopic expression of a constitutively active protein (yan(ACT)) inhibits the differentiation of multiple cell types. In an effort to identify new genes functioning downstream in the Ras/MAPK/yan pathway, we have performed a genetic screen to isolate dominant modifiers of the rough eye phenotype associated with eye-specific expression of yan(ACT). Approximately 190,000 mutagenized flies were screened, and 260 enhancers and 90 suppressors were obtained. Among the previously known genes we recovered are four RTK pathway components, rolled (MAPK), son-of-sevenless, Star, and pointed, and two genes, eyes absent and string, that have not been implicated previously in RTK signaling events. We also isolated mutations in five previously uncharacterized genes, one of which, split ends, we have characterized molecularly and have shown to encode a member of the RRM family of RNA-binding proteins.
