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Letters to Nature

Nature 431, 712-717 (7 October 2004) | doi:10.1038/nature02958; Received 3 June 2004; Accepted 23 August 2004; Published online 8 September 2004

p19ARF directly and differentially controls the functions of c-Myc independently of p53

Ying Qi1, Mark A. Gregory1, Zhaoliang Li1, Jeffrey P. Brousal1, Kimberly West1 & Stephen R. Hann1

  1. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2175, USA

Correspondence to: Stephen R. Hann1 Email: steve.hann@vanderbilt.edu

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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.