MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis

Mol Cell. 2018 Dec 6;72(5):836-848.e7. doi: 10.1016/j.molcel.2018.09.031. Epub 2018 Nov 8.


Transforming members of the MYC family (MYC, MYCL1, and MYCN) encode transcription factors containing six highly conserved regions, termed MYC homology boxes (MBs). By conducting proteomic profiling of the MB interactomes, we demonstrate that half of the MYC interactors require one or more MBs for binding. Comprehensive phenotypic analyses reveal that two MBs, MB0 and MBII, are universally required for transformation. MBII mediates interactions with acetyltransferase-containing complexes, enabling histone acetylation, and is essential for MYC-dependent tumor initiation. By contrast, MB0 mediates interactions with transcription elongation factors via direct binding to the general transcription factor TFIIF. MB0 is dispensable for tumor initiation but is a major accelerator of tumor growth. Notably, the full transforming activity of MYC can be restored by co-expression of the non-transforming MB0 and MBII deletion proteins, indicating that these two regions confer separate molecular functions, both of which are required for oncogenic MYC activity.

Keywords: BioID; MYC; TFIIF; TRRAP; cancer; histone acetylation; mass spectrometry; protein interactions; transcriptional elongation; transformation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Protein Binding
  • Protein Domains
  • Protein Interaction Mapping
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction
  • Survival Analysis
  • Transcription Factors, TFII / genetics*
  • Transcription Factors, TFII / metabolism
  • Tumor Burden
  • Xenograft Model Antitumor Assays


  • MYC protein, human
  • Protein Isoforms
  • Proto-Oncogene Proteins c-myc
  • Transcription Factors, TFII
  • transcription factor TFIIF