Professor Tyson V. Sharp

BSc (Hons), PhD
Professor of Cellular and Molecular Biology
Centre Lead, Group Leader, Research Theme Lead
Twitter
Research Focus

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.

Key Publications

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 chromosome 3p21.3-encoded gene, LIMD1, is a critical tumor suppressor involved in human lung cancer development. Proc Natl Acad Sci U S A (2008) 105(50):19932-7. PMID: 19060205

Major Funding
  • 2017-2020- Barts Charity, Novel Targeted Therapy for Renal Cancer, £337,435
  • 2016-2020- Medical Research Council, Unravelling the Mechanism of the Lung Tumour Suppressor LIMD1 from Cellular Metabolism to Malignant Transformation, £380,206
Other Activities
  • Editorial Board Membership- Nature Press: Scientific Reports
  • Reviewer for the following Journals: Oncogene, RNA, Nature Press, Journal of Molecular Medicine, PLoS Press, Nucleic Acids Research
Research

Foxler et al. A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia. EMBO Mol Med (2018) 10, e8304.

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.

PhD Studentships within the Sharp Group

Candidates interested in joining the lab to work in this research area can contact Professor Sharp by sending an email to t.sharp@qmul.ac.uk.

Currently positions are only available to self-funded students. 

*Click on image for video* Time lapse fluorescent confocal  microscopy of LIMD1-mTan (Red) and DCP2-(GFP)-tagged proteins expressed in a cancer cell. Here we used dual colour fluorescence microscopy to visualize how LIMD1 is able to form a variety of intracellular condensates/phase separations; some of which we have published (PNAS 2010, Cell Reports 2017) are mRNA processing bodies involved in microRNA-mediated gene silencing. Here we see that co-expression with the mRNA de-capping protein 2 (DCP2) produces the formation of a plethora of highly mobile and divers complexity of P-bodies and phase separated condensates.  The function of these structure in basic biology and also deregulated signalling in caner biology is a new and exciting area of investigation in our group.

*Click on image for video* An old movie (2005) LIMD1-GFP-tagged protein expressed in cancer cell and visualised with standard time lapse fluorescence microscopy. Here we can see the highly dynamic nature of LIMD1 condensates as the migrate throughout the cell cytoplasm and also fuse with each other as they progress toward the nuclear membrane. Understanding the link between phase, motility function and cancer biology is an new area of research within my team.

Other Activities

Editorial Board Membership:

  • Nature Press: Scientific Reports.

Reviewer for the following Journals:

  • Oncogene
  • RNA
  • Nature Press
  • Journal of Molecular Medicine
  • PLoS Press
  • Nucleic Acids Research

Reviewer for the following Funding Bodies:

  • MRC
  • BBSRC
  • CRUK
  • British Lung Foundation
  • L’OREAL-UNESCO for Women in Science
  • Worldwide Cancer Research
  • The Netherlands Organisation for Scientific Research

Member of:

  • The Biochemical Society
  • The British Lung Foundation
  • The British Thoracic Society
  • The British Genetics Society
  • MRC Peer Review College
Major Funding
  • 2017-2020- Barts Charity, Novel Targeted Therapy for Renal Cancer, £337,435
  • 2016-2020- Medical Research Council, Unravelling the Mechanism of the Lung Tumour Suppressor LIMD1 from Cellular Metabolism to Malignant Transformation, £380,206
  • 2015-2017- BBSRC, Characterisaiton of a new mechanism of regulation for HIF1 and the hypoxic response, £335,264.80
  • 2014-2017- BBSRC Project Grant, ‘Characterisation of a new mechanism of regulation for HIF1 and the hypoxic response,’ £335,264 PI
  • 2014-2017- CRUK PhD Studentship Award, ‘CRISPR-Cas9 genomic screen to identify novel hypoxic regulator for targeted therapy,’ worth £110,000
  • 2014-2015- Queen Mary Innovations/MRC Target Validation Funding, ‘LIMD1 loss as a target for Synthetic Lethality Drug Screen,’ £50,000 PI
  • 2013-2016- CRUK Clinical Training Fellowship Award, ‘The role of LIMD1 loss in the renal cancer stem cell aetiology,’ worth £250,000
  • 2013-2016-  MRC PhD Studentship Award, ‘Investigating the role of LIMD1 loss in the aetiology of lung cancer stem cells: a focus on metabolism,’ worth £76,200
  • 2013-2015- BBSRC Taiwan Partnering Award Two Years, PI UK International Partnership towards the advancement and discovery of novel microRNA species and regulatory proteins in stem cell biology (Ref: BB/L003945/1), £25,000
  • 2012-2015- BBSRC, The new LAW of microRNA-mediated gene silencing, £461,924.40
  • 2012-2015- Cancer Research UK, Investigating the role of LIMD1 loss in the artiology of lunch cancer stem cells, £231,692.96
  • 2012-2015- Barts Charity Project Grant, 'Induced Pluripotent Stem Cells as a platform for the study of patient-specific cellular biochemistry and assessment of personalised medicines in cancer, cardiac and endocrinological diseases,' £400,000 Co-PI 
  • 2012-2015- CRUK Project Grant, ‘Role of LIMD1 loss in lung cancer stem cell biology,’  £240,000 PI
  • 2012-2013- BBSRC Follow on Funding (FoF), ‘Pre-commercialisation validation of Stem Cell Generator as a highly efficient single transfection iPSC reprogramming vector,’ £150,000, PI
  • 2011-2014- BBSRC Project Grant, ‘The new LAW of microRNA-mediated gene silencing,’ £580,000 PI                    

 

Recent Publications

miR-132 suppresses transcription of ribosomal proteins to promote protective Th1 immunity. Hewitson JP, Shah KM, Brown N et al. EMBO Rep (2019) 20(2)
https://www.ncbi.nlm.nih.gov/pubmed/30833344

Oncometabolite induced primary cilia loss in pheochromocytoma. O'Toole SM, Watson DS, Novoselova TV et al. Endocr Relat Cancer (2019) 26(2) 165-180
https://www.ncbi.nlm.nih.gov/pubmed/30345732

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)
https://www.ncbi.nlm.nih.gov/pubmed/29930174

Deregulation of LIMD1-VHL-HIF-1α-VEGF pathway is associated with different stages of cervical cancer. Chakraborty C, Mitra S, Roychowdhury A et al. Biochem J (2018) 475(2) 1793-1806
https://www.ncbi.nlm.nih.gov/pubmed/29654110

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(2) 6282-6297
https://www.ncbi.nlm.nih.gov/pubmed/29464072

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
https://www.ncbi.nlm.nih.gov/pubmed/29066622

Ajmaline blocks INa and IKr without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters. Miller DC, Harmer SC, Poliandri A et al. Stem Cell Res (2017) 25(2) 233-244
https://www.ncbi.nlm.nih.gov/pubmed/29172153

Over expression of HIF1α is associated with inactivation of both LimD1 and VHL in renal cell carcinoma: Clinical importance. Sur S, Maurya AK, Roy A et al. Pathol Res Pract (2017) 213(2) 1477-1481
https://www.ncbi.nlm.nih.gov/pubmed/29033184

Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins. Bridge KS, Shah KM, Li Y et al. Cell Rep (2017) 20(2) 173-187
https://www.ncbi.nlm.nih.gov/pubmed/28683311

BMI-1 extends proliferative potential of human bronchial epithelial cells while retaining their mucociliary differentiation capacity. Munye MM, Shoemark A, Hirst RA et al. Am J Physiol Lung Cell Mol Physiol (2017) 312(2) L258-L267
https://www.ncbi.nlm.nih.gov/pubmed/27979861

For additional publications, please click here
Biography

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.