Arf tumor suppressor disrupts the oncogenic positive feedback loop including c-Myc and DDX5.
Tumor suppressor protein p19(ARF) (Arf; p14(ARF) in humans) functions in both p53-dependent and -independent modes to counteract hyper-proliferative signals caused by proto-oncogene activation, but its p53-independent activities remain poorly understood. Using the tandem affinity purification-tag technique, we purified Arf-containing protein complexes and identified p68 DEAD-box protein (DDX5) as a novel interacting protein of Arf. In this study, we found that DDX5 interacts with c-Myc, and harbors essential roles for c-Myc-mediated transcription and its transforming activity. Furthermore, when c-Myc was forcibly expressed, the expression level of DDX5 protein was drastically increased through the acceleration of protein synthesis of DDX5, suggesting the presence of an oncogenic positive feedback loop including c-Myc and DDX5. Strikingly, Arf blocked the physical interaction between DDX5 and c-Myc, and drove away DDX5 from the promoter of c-Myc target genes. These observations most likely indicate the mechanism by which Arf causes p53-independent tumor-suppressive activity.
Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, Shimotsuke-shi, Japan.
K
K
Tago
Faculty of Pharmacy, Department of Biochemistry, Keio University, Minato-ku, Japan.
M
M
Funakoshi-Tago
Laboratory of Signal Transduction, Department of Cell Biology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Japan.
H
H
Itoh
Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke-shi, Japan.
Y
Y
Furukawa
Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke-shi, Japan.
J
J
Kikuchi
Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Japan.
T
T
Kato
Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Japan.
K
K
Suzuki
Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, Shimotsuke-shi, Japan.
K
K
Yanagisawa
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C506751:Ddx5 protein, mouse; D053487:DEAD-box RNA Helicases