Global Regulation of Nucleotide Biosynthetic Genes by c-Myc
Open accessAbstract
BACKGROUND: The c-Myc transcription factor is a master regulator and integrates cell proliferation, cell growth and metabolism through activating thousands of target genes. Our identification of direct c-Myc target genes by chromatin immunoprecipitation (ChIP) coupled with pair-end ditag sequencing analysis (ChIP-PET) revealed that nucleotide metabolic genes are enriched among c-Myc targets, but the role of Myc in regulating nucleotide metabolic genes has not been comprehensively delineated. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that the majority of genes in human purine and pyrimidine biosynthesis pathway were induced and directly bound by c-Myc in the P493-6 human Burkitt's lymphoma model cell line. The majority of these genes were also responsive to the ligand-activated Myc-estrogen receptor fusion protein, Myc-ER, in a Myc null rat fibroblast cell line, HO.15 MYC-ER. Furthermore, these targets are also responsive to Myc activation in transgenic mouse livers in vivo. To determine the functional significance of c-Myc regulation of nucleotide metabolism, we sought to determine the effect of loss of function of direct Myc targets inosine monophosphate dehydrogenases (IMPDH1 and IMPDH2) on c-Myc-induced cell growth and proliferation. In this regard, we used a specific IMPDH inhibitor mycophenolic acid (MPA) and found that MPA dramatically inhibits c-Myc-induced P493-6 cell proliferation through S-phase arrest and apoptosis. CONCLUSIONS/SIGNIFICANCE: Taken together, these results demonstrate the direct induction of nucleotide metabolic genes by c-Myc in multiple systems. Our finding of an S-phase arrest in cells with diminished IMPDH activity suggests that nucleotide pool balance is essential for c-Myc's orchestration of DNA replication, such that uncoupling of these two processes create DNA replication stress and apoptosis.
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MYC upregulates glycolysis, DNA-synthesis, and nucleotide metabolism.
“It is established that MYC upregulates glycolysis, DNA-synthesis, and nucleotide metabolism [80]–[82].”
From Gene Expression Analysis of Zebrafish Melanocytes, Iridophores, and Retinal Pigmented Epithelium Reveals Indicators of Biological Function and Developmental Origin (2013) · cites this paper as [82]
The Discussion states that MYC upregulates glycolytic genes, and the Results show that MYC induction upregulates genes for nucleotide biosynthesis. The Discussion links these effects to providing energy and nucleotides for DNA synthesis, but our copy does not establish that MYC upregulates DNA synthesis itself. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIncreased expression of MYC induces expression of several key enzymes in nucleotide biosynthesis, including PPAT.
“Notably, increased expression of the transcription factor MYC, which is strongly associated with glutamine metabolism, induces the expression of several key enzymes in nucleotide biosynthesis, including phosphoribosyl pyrophosphate amidotransferase (PPAT)36.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [36]
Other c-myc targets involved in nucleotide biosynthesis are TS, IMPDH1, and IMPDH2.
“Other targets of c-myc that are involved in nucleotide biosynthesis are thymidylate synthase (TS) and inosine monophosphate dehydrogenase 1 (IMPDH1) and 2 (IMPDH2) (Liu et al., 2008; Mannava et al., 2008).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Liu et al., 2008
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- Authors
- Liu, Y.-C., Li, F., Handler, J., Huang, C. R. L., Xiang, Y., Neretti, N., Sedivy, J. M., Zeller, K. I., & Dang, C. V.
- Affiliations
- Johns Hopkins University (US)
- Brown University (US)
- Corresponding author
- Zeller, Karen I.
- Dang, Chi V.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-07-16
- Volume
- 3
- Issue
- 7
- Pages
- e2722
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2444028
- OpenAlex
- W1979843175
- Cited by
- 317
- References
- 52
- Citations by year
- 2026: 17 · 2025: 12 · 2024: 33 · 2023: 21 · 2022: 21 · 2021: 27 · 2020: 34 · 2019: 18 · 2018: 14 · 2017: 18 · 2016: 18 · 2015: 26 · 2014: 12 · 2013: 11 · 2012: 9
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health (R01 AG16694)
- National Institute on Aging (K25AG028753, R01AG16694, R01AG016694)
- National Cancer Institute (CA 57341, R01CA057341, CA 51497, R37CA051497, R01CA051497)
- National Institute of General Medical Sciences (R01GM41690, R01GM041690)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- c-Myc, nucleotide synthesis, purine biosynthesis, pyrimidine synthesis, IMPDH1, IMPDH2, mycophenolic acid, S phase arrest, apoptosis, replication stress, Burkitt lymphoma, transcriptional regulation, cell proliferation
- MeSH terms
- Animals, Cell Line, Fibroblasts, Gene Expression Regulation, Humans, IMP Dehydrogenase, Mice, Transgenic, Nucleotides, Proto-Oncogene Proteins c-myc, Dimerization, Cell Line, Tumor, Chromatin Immunoprecipitation, Cell Proliferation, Mice, Rats
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