My group's work focuses on the role of the tumour suppressor protein LIMD1 and its family members Ajuba and WTIP and how their deregulation in normal tissue contributes to the development of lung, renal and breast cancer.
Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes. Cell Death Dis (2021) 12, 1075. PMID: 34764236
A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia. EMBO Mol Med (2018) PMID: 29930174
Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins. Cell Rep (2017) 20(1):173-87. PMID: 28683311
The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nat Cell Biol (2012) 14(2):201-8. PMID: 22286099
LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for microRNA-mediated gene silencing. Proc Natl Acad Sci U S A (2010) 107(28):12499-504. PMID: 20616046
The current research projects within my group originate from our initial identification of LIMD1 as a specific pRB (retinoblastoma protein) binding partner (Sharp TV et al PNAS 2004). LIMD1 is on chromosome 3p21.3, often deleted in epithelial cancers. We have also shown that LIMD1 is a bona fide lung cancer tumour suppressor (Sharp TV et al PNAS 2008) and also that loss of LIMD1 expression correlates with poor patient prognosis and decreased survival with respect to breast cancer (Spendlove et al 2008).
More recently we have demonstrated the key role LIMD1 has as a scaffold protein in regulating the hypoxic response (how cells sense and respond to low levels of oxygen), through our seminal discovery of LIMD1 binding the PHD2, VHL and HIF proteins (Nature Cell Biology 2012). Furthermore, we have demonstrated that disruption of this complex and its regulation contribute to the development of lung cancer with very poor prognosis (EMBO MM 2018).
The full molecular characterization of this novel tumour suppressor is therefore the main focus of my group’s continued research. By understanding the function(s) of LIMD1 and indeed its family member proteins (Ajuba and WTIP); we can begin to understand how loss of this important tumour suppressor(s) contributes to disease pathogenesis and specifically tumorigenesis. We have also iniated new studies into targeting LIMD1 negative cancers and also the interplay of LIMD1 and LIM-domain protein with Immune-Oncology.
We are particularly focused on pancreatic, lung, prostate and ovarian cancers as areas of high unmet clinical need, working closely with colleagues in oncology at Barts Cancer Centre to translate discoveries into patient benefit.
Candidates interested in joining the lab to work in this research area can contact Professor Sharp by sending an email to firstname.lastname@example.org.
Currently positions are only available to self-funded students.
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Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes Davidson K, Grevitt P, Contreras-Gerenas MF et al. Cell Death and Disease (2021) 12(7)
Extended lifespan of bronchial epithelial cells maintains normal cellular phenotype and transcriptome integrity. O'Loughlin J, Hall RJ, Bhaker S et al. ERJ Open Res (2021) 7(2)
Extended Lifespan Bronchial Epithelial Cells Maintain Cellular Phenotype and Transcriptome Integrity Hall R, O'Loughlin J, Bhaker S et al. (2020) (10) a2298-a2298
miR-132 suppresses transcription of ribosomal proteins to promote protective Th1 immunity Hewitson JP, Shah KM, Brown N et al. EMBO Reports (2019) 20(7)
Oncometabolite induced primary cilia loss in pheochromocytoma O’Toole SM, Watson DS, Novoselova TV et al. Endocrine-Related Cancer (2019) 26(7) 165-180
A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia. Foxler DE, Bridge KS, Foster JG et al. EMBO Mol Med (2018) (1)
Deregulation of LIMD1–VHL–HIF-1α–VEGF pathway is associated with different stages of cervical cancer Chakraborty C, Mitra S, Roychowdhury A et al. Biochemical Journal (2018) 475(7) 1793-1806
LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death Wang L, Howell MEA, McPeak B et al. Oncotarget (2018) 9(7) 6282-6297
MicroRNA-155 induction via TNF-α and IFN-γ suppresses expression of programmed death ligand-1 (PD-L1) in human primary cells. Yee D, Shah KM, Coles MC et al. J Biol Chem (2017) 292(1) 20683-20693
Ajmaline blocks I
Dr Katiuscia Bianchi, Professor Claude Chelala, Dr Tatjana Crnogorac-Jurcevic, Dr Susana Godinho, Dr Gunnel Halldén, Dr Michelle Lockley, Professor Yong-Jie Lu, Dr Sarah McClelland, Dr Prabhakar Rajan, Dr Jane Sosabowski, Dr Peter Szlosarek, Professor Yaohe Wang
Mr Paul Kennedy
I obtained my PhD from St. Georges, University of London. After two postdoctoral positions in The Netherlands and USA, I returned to take up a Senior Research Fellow position at the Institute of Cancer Research in London and then UCL. I then moved to the University of Nottingham to set up my independent research group in 2005. From there I relocated to BCI. My group studies the role of the LIM domain family of adaptor proteins and their role in regulating microRNA mediates gene silencing and the hypoxic response and how deregulation of these proteins and pathways contribute to disease states including cancer.