Article ; Online: Differential regulation of FBXW7 isoforms by various stress stimuli.
2013 Volume 12, Issue 22, Page(s) 3547–3554
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 ...
| 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. |
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| MeSH term(s) | Cell Cycle/genetics ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; DNA Damage ; F-Box Proteins/genetics ; F-Box Proteins/metabolism ; F-Box-WD Repeat-Containing Protein 7 ; HCT116 Cells ; Humans ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; RNA, Messenger/metabolism ; Stress, Physiological ; Tumor Suppressor Protein p53/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism |
| Chemical Substances | Cell Cycle Proteins ; F-Box Proteins ; F-Box-WD Repeat-Containing Protein 7 ; FBXW7 protein, human ; Protein Isoforms ; RNA, Messenger ; Tumor Suppressor Protein p53 ; Ubiquitin-Protein Ligases (EC 2.3.2.27) |
| Language | English |
| Publishing date | 2013-09-24 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2146183-1 |
| ISSN | 1551-4005 ; 1538-4101 ; 1554-8627 |
| ISSN (online) | 1551-4005 |
| ISSN | 1538-4101 ; 1554-8627 |
| DOI | 10.4161/cc.26591 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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