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Videos de Conceptos Relacionados

Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

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Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
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Co-activators and Co-repressors02:04

Co-activators and Co-repressors

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Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
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RNA Polymerase II Accessory Proteins02:36

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Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
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Eukaryotic Transcription Activators02:42

Eukaryotic Transcription Activators

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Transcription activators are proteins that promote the transcription of genes from DNA to RNA. In most cases, these proteins contain two separate domains ‒ a domain that binds to DNA and a domain for activating transcription; however, in some cases, a single domain is responsible for both binding and activation of transcription, as seen in the glucocorticoid receptor and MyoD.
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
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Master Transcription Regulators02:23

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Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
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Cell Specific Gene Expression01:58

Cell Specific Gene Expression

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Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
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Video Experimental Relacionado

Updated: Nov 12, 2025

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
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La inhibición selectiva del CRAF provoca la transaccionalidad

Charles W Morgan1, Ian L Dale2, Andrew P Thomas3

  • 1Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.

Journal of the American Chemical Society
|March 22, 2021
PubMed
Resumen

Dirigirse selectivamente a CRAF (una quinasa RAF) puede activar paradójicamente la señalización RAF, contrariamente a las hipótesis. Este estudio utilizó el ligando bioortogonal (BOLT) para investigar la inhibición de CRAF, revelando implicaciones para el descubrimiento de fármacos contra el cáncer.

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Área de la Ciencia:

  • En el campo de la oncología
  • Biología molecular
  • Farmacología

Sus antecedentes:

  • El descubrimiento de fármacos específicos de la isoforma es difícil, con consecuencias desconocidas de la regulación de la isoforma.
  • Las quinasas RAF (BRAF, CRAF) son clave en la señalización de la quinasas MAP y a menudo mutan en el cáncer.
  • Los inhibidores actuales de RAF pueden causar una activación paradójica a través de CRAF, lo que lleva a la resistencia.

Objetivo del estudio:

  • Investigar los efectos de la inhibición selectiva del CRAF.
  • Explorar si la inhibición selectiva del CRAF evita la activación paradójica.
  • Demostrar la utilidad del enlace de ligando bioortogonal (BOLT) para la validación del objetivo.

Principales métodos:

  • Se utilizó el enlace bioortogonal de ligandos (BOLT) para dirigir selectivamente los inhibidores al CRAF.
  • Investigó las consecuencias de la señalización de la inhibición selectiva de CRAF.

Principales resultados:

  • Se encontró que la inhibición selectiva de CRAF promueve la activación paradójica de la señalización RAF.
  • Este hallazgo desafía la hipótesis de que la inhibición selectiva del CRAF evitaría la activación paradójica.
  • BOLT demostrado como un método para la clasificación de objetivos en etapa temprana en el descubrimiento de fármacos.

Conclusiones:

  • La inhibición selectiva de CRAF puede conducir a una activación paradójica, similar a la inhibición más amplia de RAF.
  • BOLT es una herramienta valiosa para evaluar las consecuencias de apuntar a isoformas de proteínas específicas al principio del descubrimiento de fármacos.
  • Comprender el papel de CRAF es crucial para desarrollar terapias efectivas contra el cáncer y superar la resistencia a los medicamentos.