Senior University Lecturer
Ubiquitin ligases in cancer and Parkinson’s disease
University of Cambridge
Tennis Court Road
We are interested in the unusual properties of FBPs, and have focussed much of our efforts on Fbxo7, the best example of this type of FBP. We identified Fbxo7 as an assembly factor for the proto-oncogenic D-type cyclin/Cdk6 activity. This suggested Fbxo7 would also have oncogenic activity, which we showed was the case in T lymphocytes. Upon further study, we found that Fbxo7 activity with regard to cell cycle regulation is exquisitely cell-type specific, and it can also behave as a tumour suppressor. As a regulator of cell cycle, Fbxo7 also affects cellular differentiation, and we currently investigate its impact on this in a number of different cell lineages, including haematopoietic cells and neurons. Recessive point mutations in Fbxo7 cause an atypical, early-onset form of Parkinson’s disease, and we are also characterising the defects that arise in neurons harbouring these mutated forms of Fbxo7. We also study other FBPs, including Fbxl17 and Fbxl20, which are among the most frequently rearranged genes in epithelial cancers. The challenge we face is to understand the different, complex functions of this family of signal transducing effector proteins in the context of both development and disease. We aim to tease out the cellular pathways regulated by them that can be influenced to benefit patients.
- Group Members:
Paulina Rowicka, Lisa Kent, Grasilda Zenkeviciute, Bethany Mason
- Patel SP, Randle SJ, Gibbs S, Cooke A, Laman H. Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27. Cell Mol Life Sci. 2016 Dec 3. PMID: 27915416 https://www.ncbi.nlm.nih.gov/pubmed/27915416
- Teixeira FR*, Randle SJ*, Patel SP*, Mevissen TE, Zenkeviciute G, Koide T, Komander D, Laman H. Gsk3β and Tomm20 are substrates of the SCFFbxo7/PARK15 ubiquitin ligase associated with Parkinson's disease. Biochem J. 2016 Oct 15;473(20):3563-3580. PMID: 27503909. https://www.ncbi.nlm.nih.gov/pubmed/27503909 and http://dx.doi.org/10.17863/CAM.6084
- Randle SJ, Laman H. Structure and function of Fbxo7/PARK15 in Parkinson's disease. Curr Protein Pept Sci. 2016 Mar 11. https://www.ncbi.nlm.nih.gov/pubmed/26965690
- Randle SJ, Laman H. F-box protein interactions with the hallmark pathways in cancer. Semin Cancer Biol. 2016. 36:3-17. doi: 10.1016/j.semcancer.2015.09.013. PMID: 26416465. https://www.ncbi.nlm.nih.gov/pubmed/26416465
- S. J. Randle, D. E. Nelson, S. P. Patel, and H. Laman. 2015. Fbxo7/PARK15 stabilizes p27 to ensure cell cycle arrest during erythropoiesis. 2015. J. Pathology. 2015 Jun 12. doi: 10.1002/path.4571. [Epub ahead of print]. PMID: 26095538.
- D. E. Nelson, S. J. Randle and H. Laman. 2013. Beyond ubiquitination: The atypical functions of Fbxo7 and other F-box proteins. Open Biol. 3:130131. http://dx.doi.org/10.1098/rsob.130131.
- V. S. Burchell*, D. E. Nelson*, A. Sanchez-Martinez*, M. Delgado-Camprubi, R. M. Ivatt, J. H. Pogson, S. J. Randle, S. Wray, P. A. Lewis, H. Houlden, A. Y. Abramov, J. Hardy, N. W. Wood, A. J. Whitworth, H. Laman and H. Plun-Favreau. 2013. The Parkinson’s disease genes Fbxo7 and parkin interact to mediate mitophagy. Nat Neurosci. 2013 Aug 11. doi: 10.1038/nn.3489. *Equal first authorship. Equal senior authorship. (Press release on University of Cambridge website: http://www.cam.ac.uk/research/news/genetic-mutations-linked-to-parkinsons-disease-0)
- M. Lomonosov, E. K. Meziane, H. Ye, D. E. Nelson , S. J. Randle and H. Laman. 2011. Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis. PLoS One. 6(6): e21165. doi:10.1371/journal.pone.0021165.
- E. K. Meziane*, S. J. Randle*, D. E. Nelson, M. Lomonosov, and H. Laman. 2011. Knockdown of Fbxo7 reveals its negative regulatory role in the proliferation and differentiation of B cells. J Cell Sci. 124(13):2175-2186. *Equal authorship.
- D. E. Nelson, and H. Laman. 2011. A competitive binding mechanism between Skp1 and Exportin (CRM1) controls the localisation of a subset of F-box proteins. J Biol Chem. 286(22):19804-15.