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Professor Ellen Solomon


Molecular Mechanisms of transcriptional regulation in hematopoiesis

Dr Fabien Guidez


PLZ Repression

It is known that cell differentiation and stem cell maintenance involves complex interactions of transcription factors. The formation of these protein complexes is involved in the modulation of expression of downstream target genes mediating signals for proliferation and differentiation. The crucial function of specific multi-protein complexes is achieved through waves of post-translational modifications including phosphorylation, acetylation and methylation.

The PLZF gene encodes a POZ-domain Krüppel-like Zn-finger (POK) protein (a protein with N-terminal POZ-domain and C-terminal Krüppel-like Zn-fingers). Previous studies have localised the co-repressor binding to the amino-terminal POZ domain.

We are interested in characterizing new PLZF target genes, as well as new interacting partners for this protein. We have developed two mouse models to characterize the impact of PLZF in the regulation of various developmental tissues, such as haematopoietic and germline stem cell maturation.

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Breast Cancer Genetics

Dr Jo Morris

We have a particular interest in the breast and ovarian cancer predisposition gene BRCA1. Truncating mutations in this gene cause a high risk of cancer; however, many changes in the gene are very small (alter ing just a single amino acid). Some of these are known to be pathogenic, and are potentially powerful tools in understanding the molecular fault that leads to tumour development. Sadly, most subtle BRCA1 gene changes are of unknown clinical significance, and constitute a problem for individuals and families who carry them: these patients present with a background of familial cancer and want to know their risk of future disease.

Our focus is two-fold: to use subtle changes in the gene to identify the molecular function of BRCA1, and to identify the likelihood that changes of currently unknown clinical significance are, or are not, involved in the disease process.

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Bone Biology Group

Dr. Caroline Whitehous

eBone strength is regulated by the coordinated activity of two cell types that continually remodel bone: osteoblasts that make bone matrix, and osteoclasts that remove it. Cellular processes which disrupt their activity affect bone strength by altering mass and architecture. The SQSTM1 gene is altered in some patients who have Paget's disease of the bone (PDB). They have increased, irregular bone formation that can lead to bone pain and increased susceptibility to fractures and bone deformity.

The protein product of this gene interacts with another protein called Nbr1. We have shown that if Nbr1 is shortened in mice, they also develop larger and denser bones, but this occurs through a different mechanism. In PDB the osteoclasts are overactive, whereas disruption of the Nbr1 protein in mice leads to increased activity of the osteoblasts, making more bone. Our research is based on the analysis of the function of NBR1, through identification of the interacting partners and definition of the cellular function of the protein.

Nbr1 has a number of interesting domains suggesting a role as a scaffold protein in the regulation of signalling cascades, but also its involvement in the ubiquitin pathway. We would also like to determine whether mutations in Nbr1 are linked to or cause increased bone mass in patients. However, perhaps more importantly, the identification of the detailed mechanism by which Nbr1 truncation leads to increased bone mass may become amenable to pharmacological manipulation, in order to increase bone mass in osteoporotic patients.

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Grants Awarded

Breast Cancer Genetics
Breast Cancer Campaign Fellowship, Jan 2007
Breast Cancer Campaign Studentship Oct 2007
BACR travel fellowship 2007
Guy’s & St. Thomas’ Charity Project Grant April 2007
Breakthrough Research Unit

Molecular Mechanisms of transcriptional regulation in hematopoiesis
Leukemia Research Fund Bennett Fellowship

Bone Biology Group
BBSRC PhD studentship Oct 2007
ARC Non-clinical Career Development Fellowship Jan 2007

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