EMAIL THIS PAGE TO A FRIEND

Oncotarget

MYC is a critical target of FBXW7.


PMID 25669969

Abstract

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.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

C1613 Carbenicillin, Ready Made Solution, 100 mg/mL in ethanol/water, 0.2 μm filtered
C17H18N2O6S
C106
CGS-12066 maleate salt, solid
C17H17F3N4 · C4H4O4
1295607
Glycerin, United States Pharmacopeia (USP) Reference Standard
C3H8O3
PHR1020
Glycerin, Pharmaceutical Secondary Standard; Certified Reference Material
C3H8O3
49779
Glycerol, tested according to Ph.Eur., anhydrous
C3H8O3
77067
Glycerol, analytical standard
C3H8O3
12146
Glycerol 3 M solution, 3 M
C3H8O3 · xH2O
1316004
Hydrocortisone, United States Pharmacopeia (USP) Reference Standard
C21H30O5
PHR1014
Hydrocortisone, Pharmaceutical Secondary Standard; Certified Reference Material
C21H30O5
31719
Hydrocortisone, VETRANAL, analytical standard
C21H30O5
H1300000
Hydrocortisone, European Pharmacopoeia (EP) Reference Standard
C21H30O5
Y0001092
Hydrocortisone for peak identification, European Pharmacopoeia (EP) Reference Standard
C21H30O5
15821 Klebsiella Selective Supplement, for microbiology
C17H18N2O6S
81845
Propidium iodide, ≥94% (HPLC)
C27H34I2N4
71726
Sodium dodecyl sulfate, for ion pair chromatography, ≥99.0%
C12H25NaO4S
71727
Sodium dodecyl sulfate, BioUltra, ≥99.0% (GC)
C12H25NaO4S
Y0000620
Sodium laurilsulfate, European Pharmacopoeia (EP) Reference Standard
C12H25NaO4S
71177
Sodium standard for AAS, ready-to-use, traceable to BAM, in H2O
ClNa