# New tools for studying the Myc super family in cancer

> **NIH NIH R03** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $76,250

## Abstract

Summary The Myc protooncogene is one of the most frequently dysregulated genes in human cancer. Even
small changes in Myc expression levels can support Myc-driven tumorigenesis, thus the mechanisms that control
Myc levels have been extensively scrutinized and cataloged. Less studied is the regulation of Myc activity. It is
very clear that Myc does not function in isolation, but operates within a constellation of related transcription
factors: the extended Myc network. The basic functions of each member of the extended Myc network have been
known for more than 15 years, yet how they influence Myc function is largely speculative. Further, this important
question has not been addressed using state-of-the-art molecular and genomic approaches. In this R03
application, we propose to develop the tools to assess the genomic occupancy of each member of the extended
Myc network. This tool building exercise and subsequent pilot studies are a perfect fit for the R03 funding
mechanism because they are well defined, address a critical question in cancer biology and can be completed
in the 2-year funding period with a limited budget. The extended Myc network comprises two branches, one
anchored by Max and the other anchored by Mlx. Max can interact with each Myc paralog, c-, N- and L- Myc.
Generally, Myc:Max complexes bind to genomic CANNTG E-box elements to activate transcription of genes
involved in progrowth pathways. Max can also form heterodimers with each member of the Mxd/Mad family of
transcriptional repressors and a related factor called Mnt. Mxd:Max and Mnt:Max complexes also bind CANNTG
E-box elements, but instead of activating gene expression, these complexes repress gene expression. Because
Myc:Max and Mxd(Mnt):Max complexes all bind CANNTG E-box elements, the simple model is that they occupy
similar genomic sites, but regulate expression of linked genes in the opposite direction. This model has held true
at a handful of selected binding sites and target genes, but has not been tested comprehensively. Mlx interacts
with members of the MondoA family: MondoA and ChREBP. MondoA:Mlx and ChREBP:Mlx complexes also
bind CANNTG sites and generally activate gene expression in response to changing glucose levels. The Max-
centered and Mlx-centered networks are speculated to be intertwined because Mlx can interact with a subset of
the Mxd family. How each heterocomplex of the extended Myc network identifies its genomic binding sites in the
context of the other network complexes and what dictates the functional outcome of each binding event is largely
unknown. To address the first question, we propose to perform a comprehensive ChIP-seq analysis for each
member of the extended Myc network. Because ChIP-seq is limited by the availability, specificity and affinity of
the antibodies for each factor under study, we propose to use CRISPR/Cas9 editing to fuse the same epitope
tag to the endogenous allele of each member of the extended Myc network. We will use ChIP-s...

## Key facts

- **NIH application ID:** 9876927
- **Project number:** 5R03CA234998-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Donald E Ayer
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $76,250
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876927

## Citation

> US National Institutes of Health, RePORTER application 9876927, New tools for studying the Myc super family in cancer (5R03CA234998-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9876927. Licensed CC0.

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