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Published on: May 15, 2019
FBXO32 Targets c-Myc for Proteasomal Degradation and Inhibits c-Myc Activity
Zhichao Mei1, Dawei Zhang1, Bo Hu1
1From the Key Laboratory of Aquatic Biodiversity and Conservation and.
Abstract:
FBXO32 (MAFbx/Atrogin-1) is an E3 ubiquitin ligase that is markedly up-regulated in muscle atrophy. Although some data indicate that FBXO32 may play an important role in tumorigenesis, the molecular mechanism of FBXO32 in tumorigenesis has been poorly understood. Here, we present evidence that FBXO32 targets the oncogenic protein c-Myc for ubiquitination and degradation through the proteasome pathway. Phosphorylation of c-Myc at Thr-58 and Ser-62 is dispensable for FBXO32 to induce c-Myc degradation. Mutation of the lysine 326 in c-Myc reduces c-Myc ubiquitination and prevents the c-Myc degradation induced by FBXO32. Furthermore, overexpression of FBXO32 suppresses c-Myc activity and inhibits cell growth, but knockdown of FBXO32 enhances c-Myc activity and promotes cell growth. Finally, we show that FBXO32 is a direct downstream target of c-Myc, highlighting a negative feedback regulation loop between c-Myc and FBXO32. Thus, FBXO32 may function by targeting c-Myc. This work explains the function of FBXO32 and highlights its mechanisms in tumorigenesis.
Insights
FBXO32 (MAFbx/Atrogin-1), an E3 ubiquitin ligase, targets the oncogenic protein c-Myc for degradation, inhibiting cell growth. This study reveals FBXO32’s mechanism in tumorigenesis via c-Myc regulation.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- FBXO32 (MAFbx/Atrogin-1) is an E3 ubiquitin ligase upregulated in muscle atrophy.
- Its role in tumorigenesis is poorly understood, despite potential links.
Purpose of the Study:
- To elucidate the molecular mechanism of FBXO32 in tumorigenesis.
- To investigate the interaction between FBXO32 and the oncogenic protein c-Myc.
Main Methods:
- Investigated FBXO32's targeting of c-Myc for ubiquitination and proteasomal degradation.
- Utilized phosphorylation site mutations and lysine mutations in c-Myc.
- Assessed the impact of FBXO32 overexpression and knockdown on cell growth and c-Myc activity.
Main Results:
- FBXO32 directly targets c-Myc for ubiquitination and degradation.
- c-Myc phosphorylation at Thr-58/Ser-62 is not required for FBXO32-induced degradation.
- Mutation of c-Myc lysine 326 impairs ubiquitination and degradation.
- FBXO32 overexpression inhibits cell growth by suppressing c-Myc; FBXO32 knockdown promotes growth.
- FBXO32 is a downstream target of c-Myc, forming a negative feedback loop.
Conclusions:
- FBXO32 suppresses tumorigenesis by targeting c-Myc for degradation.
- A negative feedback loop exists between c-Myc and FBXO32.
- FBXO32's mechanism in tumorigenesis involves c-Myc regulation.
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