The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator
- PMID: 23322298
- PMCID: PMC3566307
- DOI: 10.1101/gad.207720.112
The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator
Abstract
The Mediator complex is an essential transcription regulator that bridges transcription factors with RNA polymerase II. This interaction is controlled by dynamic interactions between Mediator and the CDK8 module, but the mechanisms governing CDK8 module-Mediator association remain poorly understood. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association. Our work reveals a novel mechanism regulating CDK8 module-Mediator association and suggests an expanded role for Fbw7 in transcriptional control and an unanticipated relationship with the CDK8 oncogene.
Figures
![Figure 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3566307/bin/151fig1.gif)
![Figure 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3566307/bin/151fig2.gif)
![Figure 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3566307/bin/151fig3.gif)
![Figure 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3566307/bin/151fig4.gif)
Comment in
-
Ubiquitylation: Mediation by degradation.Nat Rev Cancer. 2013 Mar;13(3):146. doi: 10.1038/nrc3471. Epub 2013 Jan 31. Nat Rev Cancer. 2013. PMID: 23363990 No abstract available.
Similar articles
-
The subunit assembly state of the Mediator complex is nutrient-regulated and is dysregulated in a genetic model of insulin resistance and obesity.J Biol Chem. 2019 Jun 7;294(23):9076-9083. doi: 10.1074/jbc.RA119.007850. Epub 2019 Apr 26. J Biol Chem. 2019. PMID: 31028171 Free PMC article.
-
A complex molecular switch directs stress-induced cyclin C nuclear release through SCFGrr1-mediated degradation of Med13.Mol Biol Cell. 2018 Feb 1;29(3):363-375. doi: 10.1091/mbc.E17-08-0493. Epub 2017 Dec 6. Mol Biol Cell. 2018. PMID: 29212878 Free PMC article.
-
Mediator kinase module and human tumorigenesis.Crit Rev Biochem Mol Biol. 2015;50(5):393-426. doi: 10.3109/10409238.2015.1064854. Epub 2015 Jul 16. Crit Rev Biochem Mol Biol. 2015. PMID: 26182352 Free PMC article. Review.
-
Suppression of Mediator is regulated by Cdk8-dependent Grr1 turnover of the Med3 coactivator.Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2500-5. doi: 10.1073/pnas.1307525111. Epub 2014 Feb 3. Proc Natl Acad Sci U S A. 2014. PMID: 24550274 Free PMC article.
-
The kinase module of the Mediator complex: an important signalling processor for the development and survival of plants.J Exp Bot. 2021 Feb 2;72(2):224-240. doi: 10.1093/jxb/eraa439. J Exp Bot. 2021. PMID: 32945869 Review.
Cited by
-
Clinical significance of FBXW7 loss of function in human cancers.Mol Cancer. 2022 Mar 26;21(1):87. doi: 10.1186/s12943-022-01548-2. Mol Cancer. 2022. PMID: 35346215 Free PMC article. Review.
-
Global and context-specific transcriptional consequences of oncogenic Fbw7 mutations.Elife. 2022 Feb 28;11:e74338. doi: 10.7554/eLife.74338. Elife. 2022. PMID: 35225231 Free PMC article.
-
Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction in MED13L syndrome fibroblasts.iScience. 2022 Jan 30;25(2):103823. doi: 10.1016/j.isci.2022.103823. eCollection 2022 Feb 18. iScience. 2022. PMID: 35198885 Free PMC article.
-
The Mediator kinase module: an interface between cell signaling and transcription.Trends Biochem Sci. 2022 Apr;47(4):314-327. doi: 10.1016/j.tibs.2022.01.002. Epub 2022 Feb 19. Trends Biochem Sci. 2022. PMID: 35193797 Free PMC article. Review.
-
Tumor Suppressor FBXW7 and Its Regulation of DNA Damage Response and Repair.Front Cell Dev Biol. 2021 Oct 25;9:751574. doi: 10.3389/fcell.2021.751574. eCollection 2021. Front Cell Dev Biol. 2021. PMID: 34760892 Free PMC article. Review.
References
-
- Akhoondi S, Sun D, von der Lehr N, Apostolidou S, Klotz K, Maljukova A, Cepeda D, Fiegl H, Dafou D, Marth C, et al. 2007. FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Res 67: 9006–9012 - PubMed
-
- Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Korner R, Greff Z, Keri G, Stemmann O, Mann M 2008. Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell 31: 438–448 - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources