Differential regulation of FBXW7 isoforms by various stress stimuli

Abstract

Fbxw7 is a tumor suppressor mutated in a wide range of human cancers. It serves as the substrate recognition component of SCF E3 ubiquitin ligases, and intensive effort was made to identify its substrates. Some of the substrates are central regulators of the cell cycle, cell fate determination, and cellular survival. Unlike the many efforts aimed at identifying novel targets, little is known about the regulation of Fbw7 isoform expression. In this study, we examined the mRNA expression of different FBXW7 isoforms during the cell cycle and after exposure to various stress stimuli. We observed that Fbw7β is induced by all the stress stimuli tested, mostly, but not exclusively, in a p53-dependent manner. In fact, FBXW7β was found to be the most potently induced p53 target gene in HCT-116 cells. Expression of FBXWα and γ is p53-independent and their responsiveness to most stress stimuli is limited. Furthermore, their pattern of stress responsiveness is very different from that of the β isoform. Under certain conditions, the same genotoxic agent stimulates induction of β and repression of α. Analysis of FACS-sorted cells in specific phases of the cell cycle by using fluorescent ubiquitination-based cell cycle indicator (FUCCI), showed a significant repression of the γ isoform during the S phase of normal cycling HCT-116 cells. Altogether, this study suggests differential regulation of the 3 Fbw7 isoforms.

Aberrant regulation of FBW7 in cancer

“…Another study showed that SREBP2 regulated miR-182 targeting FBW7, leading to a feedback pathway to regulate SREBP transcriptional activity [200, 201]. Moreover, various stress stimuli have been found to induce FBW7 expression [202]. Interestingly, various stress stimuli regulated different FBW7 isoforms.…”

Isoform‐Specific SCFFbw7 Ubiquitination Mediates Differential Regulation of PGC‐1α

“…The majority of cellular Fbw7 is the alpha isoform, with a relative isoform mRNA abundance of $1:0.07:0.01 (a: b: g) (Grim et al, 2008). Isoform expression is differentially regulated by cell cycle and various stimuli (Sionov et al, 2013). Studies of cells lacking specific Fbw7 isoforms suggest that Fbw7a accounts for almost all Fbw7 activity toward cyclin E and c-Myc (Grim et al, 2008), whereas Fbw7b degrades Notch/NICD (Sancho et al, 2013).…”

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“…Interestingly, various stress stimuli regulated different FBW7 isoforms. Specifically, FBW7β is induced by all the stress stimuli such as aphidicolin, fetal calf serum, vinblastine mostly in a p53-dependent manner, whereas expression of FBW7α and γ was responded to limited stress stimuli [202].…”

“…Another study showed that SREBP2 regulated miR-182 targeting FBW7, leading to a feedback pathway to regulate SREBP transcriptional activity [200,201]. Moreover, various stress stimuli have been found to induce FBW7 expression [202]. Interestingly, various stress stimuli regulated different FBW7 isoforms.…”