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Fbw7 and its counteracting forces in stem cells and cancer: Oncoproteins in the balance
Catherine A Cremona1, Rocio Sancho1, Markus E Diefenbacher1
1The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Abstract:
Fbw7 is well characterised as a stem cell regulator and tumour suppressor, powerfully positioned to control proliferation, differentiation and apoptosis by targeting key transcription factors for ubiquitination and destruction. Evidence in support of these roles continues to accumulate from in vitro studies, mouse models and human patient data. Here we summarise the latest of these findings, highlighting the tumour-suppressive role of Fbw7 in multiple tissues, and the rare circumstances where Fbw7 activity can be oncogenic. We discuss mechanisms that regulate ubiquitination by Fbw7, including ubiquitin-specific proteases such as USP28 that counteract Fbw7 activity and thereby stabilise oncoproteins. Deubiquitination of key Fbw7 substrates to prevent their destruction is beginning to be appreciated as an important pro-tumourigenic mechanism. As the ubiquitin-proteasome system represents a largely untapped field for drug development, the interplay between Fbw7 and its counterpart deubiquitinating enzymes in tumours is likely to attract increasing interest and influence future treatment strategies.
Insights
F-box and WD repeat domain-containing 7 (Fbw7) protein acts as a tumor suppressor by degrading oncoproteins. However, its dysregulation can promote cancer, highlighting its complex role in tumorigenesis.
Area of Science:
- Molecular Biology
- Cancer Biology
- Biochemistry
Background:
- Fbw7 is a key regulator of stem cell function and a known tumor suppressor.
- It controls cell proliferation, differentiation, and apoptosis by targeting transcription factors for degradation.
- Accumulating evidence from various studies reinforces its roles in cancer.
Purpose of the Study:
- To summarize recent findings on Fbw7's tumor-suppressive functions across multiple tissues.
- To explore the rare oncogenic roles of Fbw7.
- To discuss regulatory mechanisms of Fbw7-mediated ubiquitination, including counteracting proteases.
Main Methods:
- Review of in vitro studies
- Analysis of mouse models
- Examination of human patient data
Main Results:
- Fbw7 exhibits tumor-suppressive activity in various tissues.
- Specific conditions reveal Fbw7 can possess oncogenic properties.
- USP28 and other deubiquitinating enzymes can stabilize oncoproteins by counteracting Fbw7.
Conclusions:
- Deubiquitination of Fbw7 substrates is a critical pro-tumorigenic mechanism.
- The interplay between Fbw7 and deubiquitinating enzymes is crucial in cancer.
- Targeting the ubiquitin-proteasome system, including Fbw7 pathways, offers potential for novel cancer therapies.
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