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Regulation of APC(Cdh1) E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7
- Source :
- Cell research. 23(7)
- Publication Year :
- 2012
-
Abstract
- Fbw7 and Cdh1 are substrate-recognition subunits of the SCF- and APC-type E3 ubiquitin ligases, respectively. There is emerging evidence suggesting that both Fbw7 and Cdh1 function as tumor suppressors by targeting oncoproteins for destruction. Loss of Fbw7, but not Cdh1, is frequently observed in various human tumors. However, it remains largely unknown how Fbw7 mechanistically functions as a tumor suppressor and whether there is a signaling crosstalk between Fbw7 and Cdh1. Here, we report that Fbw7-deficient cells not only display elevated expression levels of SCF(Fbw7) substrates, including cyclin E, but also have increased expression of various APC(Cdh1) substrates. We further defined cyclin E as the critical signaling link by which Fbw7 governs APC(Cdh1) activity, as depletion of cyclin E in Fbw7-deficient cells results in decreased expression of APC(Cdh1) substrates to levels comparable to those in wild-type (WT) cells. Conversely, ectopic expression of cyclin E recapitulates the aberrant APC(Cdh1) substrate expression observed in Fbw7-deficient cells. More importantly, 4A-Cdh1 that is resistant to Cdk2/cyclin E-mediated phosphorylation, but not WT-Cdh1, reversed the elevated expression of various APC(Cdh1) substrates in Fbw7-deficient cells. Overexpression of 4A-Cdh1 also resulted in retarded cell growth and decreased anchorage-independent colony formation. Altogether, we have identified a novel regulatory mechanism by which Fbw7 governs Cdh1 activity in a cyclin E-dependent manner. As a result, loss of Fbw7 can lead to aberrant increase in the expression of both SCF(Fbw7) and APC(Cdh1) substrates. Our study provides a better understanding of the tumor suppressor function of Fbw7, and suggests that Cdk2/cyclin E inhibitors could serve as effective therapeutic agents for treating Fbw7-deficient tumors.
- Subjects :
- Male
Cyclin E
Carcinogenesis
Cyclin D
Cyclin A
Immunoblotting
Cyclin B
Models, Biological
Cdh1 Proteins
Cell Line
Mice
Cyclin D1
Cell Movement
Cell Line, Tumor
Animals
Humans
Immunoprecipitation
Phosphorylation
Molecular Biology
SKP Cullin F-Box Protein Ligases
biology
Reverse Transcriptase Polymerase Chain Reaction
Ubiquitination
Cell Biology
Cell biology
Ubiquitin ligase
Cyclin-dependent kinase complex
biology.protein
Cancer research
Original Article
Cyclin A2
Subjects
Details
- ISSN :
- 17487838
- Volume :
- 23
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Cell research
- Accession number :
- edsair.doi.dedup.....47863515c593ab0a4ab2bdd9386029fd