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In vivo quantification and perturbation of Myc-Max interactions and the impact on oncogenic potential

Academic Article
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Overview

authors

  • Raffeiner, P.
  • Rock, R.
  • Schraffl, A.
  • Hartl, M.
  • Hart, J. R.
  • Janda, Kim
  • Vogt, Peter K.
  • Stefan, E.
  • Bister, Klaus

publication date

  • October 2014

journal

  • Oncotarget  Journal

abstract

  • The oncogenic bHLH-LZ transcription factor Myc forms binary complexes with its binding partner Max. These and other bHLH-LZ-based protein-protein interactions (PPI) in the Myc-Max network are essential for the physiological and oncogenic activities of Myc. We have generated a genetically determined and highly specific protein-fragment complementation assay based on Renilla luciferase to analyze the dynamic interplay of bHLH-LZ transcription factors Myc, Max, and Mxd1 in vivo. We also applied this PPI reporter to quantify alterations of nuclear Myc-Max complexes in response to mutational events, competitive binding by the transcriptional repressor Mxd1, or perturbations by small-molecule Myc inhibitors, including recently identified potent PPI inhibitors from a Kröhnke pyridine library. We show that the specificity of Myc-Max PPI reduction by the pyridine inhibitors directly correlates with their efficient and highly specific potential to interfere with the proliferation of human and avian tumor cells displaying deregulated Myc expression. In a direct comparison with known Myc inhibitors using human and avian cell systems, the pyridine compounds reveal a unique inhibitory potential even at sub-micromolar concentrations combined with remarkable specificity for the inhibition of Myc-driven tumor cell proliferation. Furthermore, we show in direct comparisons using defined avian cell systems that different Max PPI profiles for the variant members of the Myc protein family (c-Myc, v-Myc, N-Myc, L-Myc) correlate with their diverse oncogenic potential and their variable sensitivity to the novel pyridine inhibitors.

subject areas

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cell Line, Tumor
  • Cell Proliferation
  • HEK293 Cells
  • Humans
  • Luciferases, Renilla
  • Neoplasms
  • Oxadiazoles
  • Protein Binding
  • Protein Multimerization
  • Proto-Oncogene Proteins c-myc
  • Pyridines
  • Repressor Proteins
  • Thiazoles
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Research

keywords

  • biosensor
  • cancer
  • protein-protein interactions
  • small-molecule inhibitors
  • transcription factor
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Identity

PubMed Central ID

  • PMC4253403

International Standard Serial Number (ISSN)

  • 1949-2553

Digital Object Identifier (DOI)

  • 10.18632/oncotarget.2588

PubMed ID

  • 25326649
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Additional Document Info

start page

  • 8869

end page

  • 8878

volume

  • 5

issue

  • 19

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