Video Experimental Relacionado
Updated: Jun 29, 2026
09:18
Spheroid Assay to Measure TGF-β-induced Invasion
Published on: November 16, 2011
El BRAF oncogénico induce la senescencia y la apoptosis a través de vías mediadas por la proteína secretada IGFBP77
Narendra Wajapeyee1, Ryan W Serra, Xiaochun Zhu
1Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cell
|February 13, 2008
Resumen
La activación del oncogén BRAFV600E desencadena la secreción de IGFBP7, que paradójicamente detiene el crecimiento celular. Este descubrimiento ofrece nuevos conocimientos sobre el desarrollo del melanoma y posibles objetivos terapéuticos.
Área de la Ciencia:
- Oncología Oncología.
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
Sus antecedentes:
- La activación oncogénica puede, paradójicamente, inhibir la proliferación celular a través de la senescencia o la apoptosis.
- Las vías moleculares precisas que median este efecto no se comprenden completamente.
Objetivo del estudio:
- Para identificar genes involucrados en el bloqueo de proliferación inducido por BRAFV600E en células primarias humanas.
- Aclarar el papel de las proteínas secretadas en la senescencia y la apoptosis mediadas por oncogenes.
Principales métodos:
- Cribado de interferencia de ARN en todo el genoma en fibroblastos primarios humanos y melanocitos.
- Análisis de la vía de señalización BRAF-MEK-ERK.
- Evaluación de la apoptosis utilizando la regulación ascendente de BNIP3L.
- Pruebas in vitro de IGFBP7 recombinante (rIGFBP7) en líneas celulares de melanoma.
- Estudios in vivo de supresión tumoral en ratones xenograftados.
- Análisis inmunohistoquímico de muestras de piel humana, nevi y melanoma.
Principales resultados:
- Se identificaron 17 genes como esenciales para el bloqueo de proliferación mediado por BRAFV600E.
- La proteína 7 de unión al factor de crecimiento similar a la insulina (IGFBP7) juega un papel crucial en la senescencia y la apoptosis inducidas por BRAFV600E.
- La expresión de BRAFV600E conduce a la síntesis y secreción de IGFBP7, que inhibe la señalización BRAF-MEK-ERK.
- IGFBP7 también regula la proteína proapoptótica BNIP3L.
- rIGFBP7 induce la apoptosis en las células de melanoma BRAFV600E positivas y suprime el crecimiento tumoral in vivo.
- La pérdida de la expresión de IGFBP7 está implicada como un evento crítico en el desarrollo del melanoma.
Conclusiones:
- IGFBP7 es un mediador clave de la senescencia y la apoptosis inducidas por BRAFV600E.
- IGFBP7 actúa a través de mecanismos autocrinos / paracrinos para inhibir la señalización oncogénica y promover la muerte celular.
- IGFBP7 representa un objetivo terapéutico potencial para el melanoma positivo para BRAFV600E.
- La pérdida de IGFBP7 es un factor significativo en la génesis del melanoma.
Videos de Conceptos Relacionados
02:38The Ras Gene
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Ras is a superfamily...
03:03mTOR Signaling and Cancer Progression
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
01:31The Intrinsic Apoptotic Pathway
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
01:07MAPK Signaling Cascades
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
01:16TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
03:03mTOR Signaling and Cancer Progression
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...