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Investigation into the molecular mechanisms of inherited renal cancer

Nahorski, Michael Stefan (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

Birt Hogg Dubé (BHD) syndrome is an inherited cancer susceptibility syndrome characterised by the development of fibrofolliculomas on the face and upper torso, and increased risk of lung cysts, spontaneous pneumothorax and renal cancer. The findings presented in this thesis advance knowledge into how the mutations in the FLCN gene cause the phenotypes associated with BHD syndrome, and provides novel insights into the functions of folliculin within the cell. The results presented provide further evidence of the association between BHD syndrome and increased risk of colorectal cancer in a subset of BHD syndrome families, and suggest that this association appears restricted to those patients with an exon 11 mononucleotide tract mutation. Evolutionary conservation analysis across the FLCN sequence suggests that pathogenic mutations could be expected throughout the gene, and identifies a region between codons 100-230 of increased evolutionary significance. The experiments undertaken demonstrate a practical strategy for determining the pathogenicity of non-truncating folliculin variants in vitro, and indicate that loss of protein stability is the main mechanism of pathogenicity for the previously reported non-truncating mutations within FLCN. Finally, this thesis reports the first identification of p0071 as a folliculin interacting protein. Folliculin deficiency exerts a functional impact on previously reported p0071 functions inducing RhoA signalling upregulation, mitotic defects and disruption of cell junctions. These results demonstrate the potential efficacy of using inhibitors downstream of RhoA as therapeutic targets in BHD tumours with dyregulated RhoA signaling, and provide novel directions for research into BHD syndrome.

Type of Work:Ph.D. thesis.
Supervisor(s):Maher, Eamonn
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Medical and Molecular Genetics, Medical School
Additional Information:

Research related to this thesis is published in:

1. Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer.
Nahorski MS, Lim DH, Martin L, Gille JJ, McKay K, Rehal PK, Ploeger HM, van Steensel M, Tomlinson IP, Latif F, Menko FH, Maher ER.
J Med Genet. 2010 Jun;47(6):385-90

2. Birt Hogg-Dubé syndrome-associated FLCN mutations disrupt protein stability.
Nahorski MS, Reiman A, Lim DH, Nookala RK, Seabra L, Lu X, Fenton J, Boora U, Nordenskjöld M, Latif F, Hurst LD, Maher ER.
Hum Mutat. 2011 Aug;32(8):921-9.
http://dx.doi.org/10.1002/humu.21519
Epub 2011 Jul 12

3. A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene.
Lim DH, Rehal PK, Nahorski MS, Macdonald F, Claessens T, Van Geel M, Gijezen L, Gille JJ, Giraud S, Richard S, van Steensel M, Menko FH, Maher ER.
Hum Mutat. 2010 Jan;31(1):E1043-51

4. Therapeutic targeting the loss of the birt-hogg-dube suppressor gene.
Lu X, Wei W, Fenton J, Nahorski MS, Rabai E, Reiman A, Seabra L, Nagy Z, Latif F, Maher ER.
Mol Cancer Ther. 2011 Jan;10(1):80-9.

5. Folliculin interacts with p0071 and regulates RhoA signalling, cell polarisation and cytokinesis
Michael S Nahorski, Laurence Seabra, AniaStraatman-Iwanowska, Aileen Wingenfeld, Anne Reiman, Xiaohong Lu, Paul Gissen, Mechthild Hatzfeld, Eamonn R Maher
(for submission to J Cell Biol)

Subjects:QH301 Biology
QH426 Genetics
RB Pathology
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:3663
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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