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Related Concept Videos

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

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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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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

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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.
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Master Transcription Regulators02:23

Master Transcription Regulators

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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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Related Experiment Video

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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Selective CRAF Inhibition Elicits Transactivation.

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
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Summary

Targeting CRAF (a RAF kinase) selectively may paradoxically activate RAF signaling, contrary to hypotheses. This study used bio-orthogonal ligand tethering (BOLT) to investigate CRAF inhibition, revealing implications for cancer drug discovery.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Discovering isoform-specific drugs is difficult, with unknown consequences of isoform regulation.
  • RAF kinases (BRAF, CRAF) are key in MAP kinase signaling and often mutated in cancer.
  • Current RAF inhibitors can cause paradoxical activation via CRAF, leading to resistance.

Purpose of the Study:

  • To investigate the effects of selective CRAF inhibition.
  • To explore if CRAF-selective inhibition bypasses paradoxical activation.
  • To demonstrate the utility of bio-orthogonal ligand tethering (BOLT) for target validation.

Main Methods:

  • Utilized bio-orthogonal ligand tethering (BOLT) to selectively target inhibitors to CRAF.
  • Investigated the downstream signaling consequences of selective CRAF inhibition.

Main Results:

  • Selective CRAF inhibition was found to promote paradoxical activation of RAF signaling.
  • This finding challenges the hypothesis that CRAF-selective inhibition would bypass paradoxical activation.
  • Demonstrated BOLT as a method for early-stage target triage in drug discovery.

Conclusions:

  • Selective CRAF inhibition can lead to paradoxical activation, similar to broader RAF inhibition.
  • BOLT is a valuable tool for assessing the consequences of targeting specific protein isoforms early in drug discovery.
  • Understanding CRAF's role is crucial for developing effective cancer therapies and overcoming drug resistance.