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Published on: July 25, 2017
Arf tumor suppressor disrupts the oncogenic positive feedback loop including c-Myc and DDX5
K Tago1, M Funakoshi-Tago2, H Itoh3
1Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, Shimotsuke-shi, Japan.
Abstract:
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.
Insights
Tumor suppressor p19(ARF) inhibits cancer by disrupting the c-Myc and DDX5 interaction. This study reveals Arf’s p53-independent mechanism, blocking oncogenic transcription and tumor growth.
Area of Science:
- Molecular Biology
- Oncology
- Cellular Biology
Background:
- The tumor suppressor p19(ARF) counters hyper-proliferation via p53-dependent and -independent pathways.
- p19(ARF)'s p53-independent functions, particularly in oncogene-induced proliferation, are not well understood.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying p19(ARF)'s p53-independent tumor-suppressive activities.
- To identify novel Arf-interacting proteins and their roles in oncogenic signaling.
Main Methods:
- Tandem affinity purification to isolate Arf-containing protein complexes.
- Co-immunoprecipitation and Western blotting to confirm protein interactions.
- Analysis of gene expression and protein synthesis rates.
Main Results:
- p19(ARF) interacts with the DEAD-box protein DDX5, a key regulator of c-Myc.
- DDX5 facilitates c-Myc-mediated transcription and transforming activity.
- c-Myc overexpression enhances DDX5 protein synthesis, forming a positive feedback loop.
- p19(ARF) disrupts the DDX5-c-Myc interaction and displaces DDX5 from c-Myc target gene promoters.
Conclusions:
- p19(ARF) exerts p53-independent tumor suppression by inhibiting the c-Myc/DDX5 oncogenic complex.
- This mechanism involves blocking DDX5's role in c-Myc transcription and transforming activity.
- The findings reveal a novel pathway for Arf-mediated tumor suppression.
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