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Updated: Feb 2, 2026
Identification of Functional Protein Regions Through Chimeric Protein Construction
Published on: January 8, 2019
MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis
Manpreet Kalkat1, Diana Resetca1, Corey Lourenco1
1Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Abstract:
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.
Insights
The MYC family proteins are crucial for cell transformation. Two key regions, MYC homology boxes 0 and II, have distinct roles in tumor initiation and growth, both essential for MYC
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The MYC family (MYC, MYCL1, MYCN) are transcription factors vital for cell growth.
- These proteins contain six conserved regions known as MYC homology boxes (MBs).
- Understanding the function of these MBs is critical for deciphering MYC's role in cancer.
Purpose of the Study:
- To investigate the functional roles of MYC homology boxes (MBs) in MYC family protein transformation.
- To identify specific MBs essential for MYC's oncogenic activities.
- To elucidate the molecular mechanisms by which MBs contribute to tumor development.
Main Methods:
- Proteomic profiling of MYC homology box interactomes.
- Comprehensive phenotypic analyses of MYC mutants.
- Assays to assess histone acetylation and transcription elongation.
Main Results:
- Half of MYC interactors bind via one or more MBs.
- MYC homology boxes 0 (MB0) and II (MBII) are essential for transformation.
- MBII mediates histone acetylation for tumor initiation; MB0 interacts with transcription elongation factors for tumor growth acceleration.
- MB0 and MBII possess distinct, non-redundant functions required for oncogenic MYC activity.
Conclusions:
- MYC homology boxes 0 and II are critical functional domains of MYC proteins.
- MBII is essential for MYC-driven tumor initiation via acetylation.
- MB0 accelerates tumor growth by regulating transcription elongation.
- Both MB0 and MBII are indispensable for MYC's full oncogenic potential.
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