Abstract
Increased expression of the oncogenic transcription factor c-Myc causes unregulated cell cycle progression1. c-Myc can also cause apoptosis, but it is not known whether the activation and/or repression of c-Myc target genes mediates these diverse functions of c-Myc. Because unchecked cell cycle progression leads to hyperproliferation and tumorigenesis, it is essential for tumour suppressors, such as p53 and p19ARF (ARF), to curb cell cycle progression in response to increased c-Myc (refs 2, 3). Increased c-Myc has previously been shown to induce ARF expression, which leads to cell cycle arrest or apoptosis through the activation of p53 (ref. 4). Here we show that ARF can inhibit c-Myc by a unique and direct mechanism that is independent of p53. When c-Myc increases, ARF binds with c-Myc and dramatically blocks c-Myc's ability to activate transcription and induce hyperproliferation and transformation. In contrast, c-Myc's ability to repress transcription is unaffected by ARF and c-Myc-mediated apoptosis is enhanced. These differential effects of ARF on c-Myc function suggest that separate molecular mechanisms mediate c-Myc-induced hyperproliferation and apoptosis. This direct feedback mechanism represents a p53-independent checkpoint to prevent c-Myc-mediated tumorigenesis.
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Acknowledgements
We thank C. Sherr and S. Hiebert for pCMV5-ARF and ARF-/- MEFs, G. Zambetti for DKO MEFs, R. DePinho for htert-SEAP and cul1-luc, L. Penn for gadd45-luc and pdgfβr-luc, E. Ruley for p53-/- MEFs, J. Pietenpol for REF 112 cells, and J. Sedivy for HO16 cells. We also thank R. Eisenman for critical review of the manuscript. This work was supported by grants from NIH to S.R.H.
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Supplementary information
Supplementary Methods
Methods used for this study not described in the main article, including details on construction of expression vectors, cell culture, transfection, generation of cell lines, all PCR primers used, northern blot analysis, cell proliferation and apoptosis assays. (DOC 46 kb)
Supplementary Figure 1
Analysis of the effects of ARF on additional c-Myc target gene reporters and on the expression of additional endogenous c-Myc target genes not shown in main article. (PPT 115 kb)
Supplementary Figure 2
Co-immunoprecipitation analysis of ARF and c-Myc with Max, which was described, but not shown, in main article. (PPT 54 kb)
Supplementary Figure 3
Immunoblot analysis of c-Myc, c-MycER, ARF, p53, and p21 protein expression in the cell lines used for this study. (PPT 186 kb)
Supplementary Figure Legends
Legends to Supplementary Figures 1-3. (DOC 21 kb)
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Qi, Y., Gregory, M., Li, Z. et al. p19ARF directly and differentially controls the functions of c-Myc independently of p53. Nature 431, 712–717 (2004). https://doi.org/10.1038/nature02958
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DOI: https://doi.org/10.1038/nature02958
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