title: Differential effects on ARF stability by normal versus oncogenic levels of c-Myc expression.
abstract: 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.
authors.affiliation: 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.
authors.forename: Delin
authors.initials: D
authors.lastname: Chen
authors.forename: Ning
authors.initials: N
authors.lastname: Kon
authors.forename: Jiayun
authors.initials: J
authors.lastname: Zhong
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Zhang
authors.forename: Long
authors.initials: L
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D004249:DNA Damage; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF; C530813:TRIP12 protein, human; D044767:Ubiquitin-Protein Ligases