期刊
MOLECULAR CELL
卷 51, 期 1, 页码 46-56出版社
CELL PRESS
DOI: 10.1016/j.molcel.2013.05.006
关键词
-
资金
- National Cancer Institute of the National Institutes of Health [R01CA169246, 2PO1CA080058, 2PO1 CA097403]
- leukemia and lymphoma society
- National Natural Science Foundation of China [31071193]
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 nnRNA 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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