Global Regulation of Nucleotide Biosynthetic Genes by c-Myc

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.

OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors

“…Collectively, our findings suggest that individual genes encoding rate-limiting proteins involved in basic cell biological processes respond to the difference between physiological and supraphysiological MYC levels and that OmoMYC specifically inhibits tumor cell growth since it suppresses expression of this group of genes. A similar picture has emerged from studies of nucleotide biosynthesis genes: despite pervasive binding of MYC to promoters of nucleotide biosynthetic enzymes 46 , deregulation of a single rate-limiting enzyme, phosphoribosylpyrophosphate synthetase 2 (PRPS2), promotes the increased nucleotide biosynthesis of MYC-transformed cells 47 . A complete understanding of how to mimic OmoMYC´s efficacy with small molecule inhibitors will therefore require an analysis of its target genes in an in vivo setting.…”

Metabolism and proliferation share common regulatory pathways in cancer cells

“…Both c-Myc and E2F1 are important regulators of cell cycle, and it has been suggested that c-Myc metabolic gene targets are regulated in a cell-cycle-dependent way. Indeed, after induction of energy metabolism-and ribosomal biogenesis-related genes during the G 1 phase, c-Myc induces E2F1 expression as cells enter into the S phase, that together with c-Myc activates genes involved in nucleotides biosynthesis and DNA replication (Liu et al, 2008). There is no need to discuss the importance of Ras oncogenes in the control of cell proliferation and tumor development (Drosten et al, 2010).…”

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

“…All these results point to the enigmatic roles and underlying mechanisms for cMyc yet to be further elucidated under developmental or oncogenic circumstances. cMyc has been extensively documented to regulate glucose, glutamine and nucleotides metabolism [7,[40][41][42][43], nevertheless, it is unclear whether cMyc also controls the serine/glycine metabolism, especially under nutrient-deprived conditions.…”