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Related Concept Videos

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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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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Combinatorial gene control is the synergistic action of several transcriptional factors to regulate the expression of a single gene. The absence of one or more of these factors may lead to a significant difference in the level of gene expression or repression.
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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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Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function.

Benjamin Bourgeois1, Tianshu Gui2, Diana Hoogeboom2

  • 1Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.

Cell Reports
|July 28, 2021
PubMed
Summary

Forkhead box O4 (FOXO4) protein activity is regulated by β-catenin binding. This interaction, modulated by phosphorylation, enhances FOXO4

Keywords:
FOXO signalingICATNMR spectroscopyWnt signalingcancerintrinsically disordered proteinsphosphorylationpost-translational modificationstructural biologyβ-catenin

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Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Transcription Regulation

Background:

  • Transcription factors often contain intrinsically disordered regions (IDRs) that play regulatory roles.
  • Understanding how IDRs interact with structured co-regulators is crucial for deciphering gene regulation.

Purpose of the Study:

  • To elucidate the molecular mechanism by which the co-regulator β-catenin regulates the transcription factor FOXO4.
  • To investigate the role of post-translational modifications and protein-protein interactions in FOXO4 activity.

Main Methods:

  • Biochemical assays to study protein-protein interactions between FOXO4 and β-catenin.
  • Phosphorylation site mapping using mass spectrometry.
  • Analysis of transcriptional activity in response to co-regulator binding and inhibition.

Main Results:

  • The disordered C-terminal region of FOXO4 binds β-catenin at two sites, regulated by PKB/AKT and CK1 phosphorylation.
  • β-catenin binding disrupts an autoinhibitory interaction within FOXO4, enhancing its transcriptional activity.
  • The inhibitor ICAT can bind β-catenin simultaneously with FOXO4, suggesting a role in switching signaling pathways.

Conclusions:

  • Post-translational modifications and co-factor binding dynamically regulate FOXO4 function through its intrinsically disordered regions.
  • The interplay between FOXO4, β-catenin, and ICAT provides a molecular switch between anti-proliferative and pro-proliferative signaling pathways.