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694978.pdf (1.72 MB)

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Data de publicació

2014-12-26

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cc-by (c) Sato, Mai et al., 2014
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/178607

MYC is a critical target of FBXW7

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Recurs relacionat

https://doi.org/10.18632/oncotarget.3203

Resum

MYC deregulation is a driver of many human cancers. Altering the balance of MYC protein levels at the level of transcription, protein stability, or turnover is sufficient to transform cells to a tumorigenic phenotype. While direct targeting of MYC is difficult, specific genetic vulnerabilities of MYC-deregulated cells could be exploited to selectively inhibit their growth. Using a genome-wide shRNA screen, we identified 78 candidate genes, which are required for survival of human mammary epithelial cells with elevated MYC levels. Among the candidates, we validated and characterized FBXW7, a component of the SCF-like ubiquitin ligase complex that targets MYC for proteasomal degradation. Down-regulation of FBXW7 leads to synergistic accumulation of cellular and active chromatin-bound MYC, while protein levels of other FBXW7 targets appear unaffected. Over a four-week time course, continuous FBXW7 down-regulation and MYC activation together cause an accumulation of cells in S-phase and G2/M-phase of the cell cycle. Under these conditions, we also observe elevated chromatin-bound levels of CDC45, suggesting increased DNA replication stress. Consistent with these results, FBXW7 down-regulation alone decreases the survival of T47D breast cancer cells. These results establish that FBXW7 down-regulation is synthetic lethal with MYC, and that MYC is a critical target of FBXW7 in breast epithelial cells.

Matèries

Càncer, Proteïnes, Cèl·lules

Matèries (anglès)

Cancer, Proteins, Cells

Citació

Col·leccions

Articles publicats en revistes (Patologia i Terapèutica Experimental)

Citació

SATO, Mai, et al. MYC is a critical target of FBXW7. Oncotarget. 2014. Vol. 6, num. 5, pags. 3292-3305. ISSN 1949-2553. [consulted: 3 of August of 2026]. Available at: https://hdl.handle.net/2445/178607

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