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Varias vías supresoras de tumores regulan negativamente la telomerasa
Shiaw Yih Lin1, Stephen J Elledge
1Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Cell
|July 3, 2003
Resumen
La telomerasa (hTERT) está reprimida en la mayoría de las células pero activa en el cáncer. Este estudio identificó tres vías supresoras de tumores (Mad1 / c-Myc, SIP1 y Menin) que regulan hTERT, revelando conocimientos sobre el desarrollo del cáncer.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Investigación de Investigación del Cáncer.
- Genética La genética.
Sus antecedentes:
- La expresión de la telomerasa es típicamente reprimida en las células somáticas pero activa en las células madre y muchos cánceres humanos.
- Se supone que la actividad de la telomerasa es crucial para la tumorigénesis y el mantenimiento de las propiedades de las células madre.
- Comprender la regulación de la telomerasa es clave para desarrollar terapias contra el cáncer.
Objetivo del estudio:
- Para identificar los reguladores negativos de la expresión de la telomerasa humana y la transcriptasa inversa (hTERT).
- Para aclarar el papel del supresor tumoral y las vías oncogénicas en el control de la actividad de la telomerasa.
Principales métodos:
- Utilizó una pantalla genética general para identificar los reguladores negativos de hTERT.
- Investigó las vías Mad1/c-Myc, TGF-beta/SIP1 y Menin en relación con la represión de hTERT.
- Evaluó el impacto del agotamiento de Menin en los fibroblastos humanos primarios y los fenotipos de transformación.
Principales resultados:
- Se identificaron tres vías de supresión tumoral/oncogénica distintas involucradas en la represión de hTERT: Mad1/c-Myc, SIP1 (un objetivo de TGF-beta) y Menin.
- Confirmó el papel de la vía Mad1/c-Myc en la regulación de hTERT.
- Se ha demostrado que SIP1 media la represión de hTERT regulada por TGF-beta.
- Menin mostrado directamente reprime hTERT y su agotamiento inmortaliza los fibroblastos y promueve la transformación.
Conclusiones:
- Múltiples vías supresoras de tumores y vías oncogénicas se coordinan para reprimir la expresión de hTERT.
- La reactivación de la telomerasa en los tumores humanos probablemente ocurra a través de mutaciones oncogénicas que interrumpen estas vías reguladoras.
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