期刊
CANCER BIOLOGY & THERAPY
卷 23, 期 1, 页码 348-357出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15384047.2022.2061279
关键词
Fbxl8; c-myc; ubiquitin ligase; cell cycle; cancer
类别
资金
- National Institutes of Health [R01CA093237]
Overexpression of c-myc is a common feature in many cancer types, and its degradation is mediated by ubiquitin-dependent degradation. Fbxl8, a new E3 ligase, targets c-myc for selective degradation via the SCF ubiquitin ligase complex, independent of the primary regulator Fbxw7. Loss of Fbxl8 increases c-myc protein levels and cell division, while overexpression of Fbxl8 reduces c-myc protein levels.
Overexpression of c-myc via increased transcription or decreased protein degradation is common to many cancer etiologies. c-myc protein degradation is mediated by ubiquitin-dependent degradation, and this ubiquitylation is regulated by several E3 ligases. The primary regulator is Fbxw7, which binds to a phospho-degron within c-myc. Here, we identify a new E3 ligase for c-myc, Fbxl8 (F-box and Leucine Rich Repeat Protein 8), as an adaptor component of the SCF (Skp1-Cullin1-F-box protein) ubiquitin ligase complex, for selective c-myc degradation. SCFFbxl8 binds and ubiquitylates c-myc, independent of phosphorylation, revealing that it regulates a pool of c-myc distinct from SCFFbxw7. Loss of Fbxl8 increases c-myc protein levels, protein stability, and cell division, while overexpression of Fbxl8 reduces c-myc protein levels. Concurrent loss of Fbxl8 and Fbxw7 triggers a robust increase in c-myc protein levels consistent with targeting distinct pools of c-myc. This work highlights new mechanisms regulating c-myc degradation.
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