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Mol Cell. 2013 Jul 11;51(1):46-56. doi: 10.1016/j.molcel.2013.05.006. Epub 2013 Jun 6.

Differential effects on ARF stability by normal versus oncogenic levels of c-Myc expression.

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Institute for Cancer Genetics and Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.


ARF suppresses aberrant cell growth upon c-Myc overexpression by activating p53 responses. Nevertheless, the precise mechanism by which ARF specifically restrains the oncogenic potential of c-Myc without affecting its normal physiological function is not well understood. Here, we show that low levels of c-Myc expression stimulate cell proliferation, whereas high levels inhibit by activating the ARF/p53 response. Although the mRNA levels of ARF are induced in both scenarios, the accumulation of ARF protein occurs only when ULF-mediated degradation of ARF is inhibited by c-Myc overexpression. Moreover, the levels of ARF are reduced through ULF-mediated ubiquitination upon DNA damage. Blocking ARF degradation by c-Myc overexpression dramatically stimulates the apoptotic responses. Our study reveals that ARF stability control is crucial for differentiating normal (low) versus oncogenic (high) levels of c-Myc expression and suggests that differential effects on ULF- mediated ARF ubiquitination by c-Myc levels act as a barrier in oncogene-induced stress responses.

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