Abstract
BackgroundThe 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 FindingsHere, 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/SignificanceTaken 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.
Highlights
MYC, which encodes the c-Myc transcription factor, is frequently altered in human cancers [1,2,3]
From our previous genome-wide mapping of Myc binding sites via coupling chromatin immunoprecipitation with pair-end ditag sequencing analysis (ChIP-PET) in P493-6 cells [33], we found that among sets of genes bound by Myc, nucleic acid metabolism is one of the most significantly enriched functional class based on Gene Ontology categorization through the PANTHER database
The P493-6 cell line, an EBV immortalized B lymphocyte engineered with a tetracycline (Tet)repressible c-MYC expression vector, is considered as an in vitro Burkitt’s lymphoma model [45]
Summary
MYC, which encodes the c-Myc ( termed Myc) transcription factor, is frequently altered in human cancers [1,2,3]. Subsequent to initial studies demonstrating that forced expression of MYC in lymphoid tissues resulted in lymphoid hyperplasia and lymphomas, virtually all other studies of constitutive or inducible MYC in tissues from skin to liver resulted in neoplastic transformation of the targeted tissue. Studies with these models have revealed that MYC mediated tumorigenesis includes the concurrent activation of cell growth and proliferation along with inactivation of apoptotic pathways in a tissue specific fashion [8,9]. 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
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