Professor Heike Laman
Position: Head of Department
Personal home page:
http://www.path.cam.ac.uk/research/investigators/laman/research.html
PubMed journal articles - click here
Professor Heike Laman is pleased to consider applications from prospective PhD students.
F-box proteins (FBPs) are the substrate-recruiting subunits of SCF (Skp1-cullin1-FBP)-type E3 ubiquitin ligases, but ubiquitinated substrates have been identified for only a few of the sixty-nine FBPs identified in humans. The major aim of my laboratory?s research is to investigate how the mis-regulation of individual F-box proteins causes human diseases. One FBP that we study is Fbxo7/PARK15, which is assoicated with both cancer and Parkinson?s disease. We identified a surprising, non-canonical activity for Fbxo7, which acts as an assembly factor for D-type cyclin/Cdk6 complexes. We want to understand how this FBP integrates cellular signals to impact on G1 cell cycle regulators to affect cellular decision making. Mutations in Fbxo7 are also associated with an atypical, early onset Parkinson's disease, and we are characterising the recessive mutations in Fbxo7 that give rise to neurodegenerative disease. We use mouse models which have compromised Fbxo7/PARK15 expression to study its functional effects in vivo. We also study other FBPs that we have identified as being among the most frequently rearranged genes in epithelial cancers. The challenge we face is to understand the network of functions that has been compromised by the loss of the FBP that is causing disease. We aim to tease out the cellular pathways regulated by them that can be influenced to benefit patients.
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1) Structure and function of Fbxo7/PARK15 in PD. S. Randle and H. Laman 2015. Curr Protein Pep Sc. In press. 2) 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. 3) 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. 4) H. J. Kuiken, D. A. Egan, H. Laman, R. Bernards, R. Beijersbergen, A. M. Dirac. 2012. Identification of F-box only protein 7 as a negative regulator of NF-?B signaling. J Cell Mol Med. 16(9):2140-9. 5) M. Gooding, S. Tudzarova, R. J. Worthington, M. I. Simone, D. Lagos, A. Rebstock, C. Visintin, S. R. Kingsbury, H. Laman, C. Boshoff, G. H. Williams, K. Stoeber, and D. L. Selwood. 2011. Exploring the interaction between siRNA and the SMoC cellular transporters: implications for small molecule delivery of oligonucleotides. Chem Biol & Drug Design 79(1):9-21. 6) 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. JCell Sci. 124(13):2175-2186. &Equal authorship. 7) 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. 8) 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. 9) R. J. Kirk, H. Laman*, P. P. Knowles, J. Murray-Rust, M. Lomonosov, E. K. Meziane and N. Q. McDonald*. 2008. Structure of a conserved dimerisation domain within Fbxo7 and PI31 links an E3 ubiquitin ligase and immunoproteasome regulation. J Biol Chem. 283(32):22325-35. *Co-corresponding author. 10) M. Okuyama*, H. Laman*, S. Kingsbury*, C. Visintin, E. Leo, K. Eward, K. Stoeber, C. Boshoff, G. Williams and D. Selwood. 2007. Small molecule mimics of an alpha-helix for rapid and efficient protein delivery into cells. Nat Methods. 4(2):153-9. *Equal first authorship.
