Julian Downward

Julian Downward obtained his bachelor's degree in Natural Sciences from Cambridge University and then studied for his Ph.D. degree in Biochemistry in the laboratory of Michael Waterfield at the Imperial Cancer Research Fund in London, where he established in 1984 a link between a retroviral gene (v-erbB) and a cellular growth regulatory protein, the EGF receptor, leading to an ISI "citation classic" publication.

In 1986, he moved to Robert Weinberg's laboratory at the Whitehead Institute at the Massachusetts Institute of Technology in Cambridge, MA, where he began work on Julian Downard the role of Ras proteins in human cancer.

In 1989 he started his own lab at the Imperial Cancer Research Fund in London, now renamed the Cancer Research UK London Research Institute. The lab has provided critical insights into the molecular mechanisms of function and regulation of oncogenic proteins of the Ras family and their importance in human tumours.

He has a long held interest in functional genomics, coordinating a number of programmes in this area. He holds honorary professorships at University College London and at St. Bartholomew's Hospital Medical School, London. He has published over 150 papers in international scientific journals. He was elected to the membership of the European Molecular Biology Organisation in 1995 and was made a Fellow of the Royal Society in 2005. He belongs to the Editorial Boards of the journals Cell, Science and Molecular Cell.

Signal Transduction Laboratory
We are interested in the mechanisms by which regulatory signals affecting the growth and survival of cells are transmitted from cell surface receptors to intracellular targets. We study both the normal function of these signaling pathways and also the defects in their regulation found in cancerous cells.

Much of the work in the laboratory has focused on the RAS family of oncogenes and the signaling pathways that they control. While the early signalling pathways activated by Ras are now well characterised and the transcriptional programmes they induce have been documented using microarray technology (e.g. Schulze et al., Genes & Development 2001; 15: 981 and Schulze et al., Mol. Biol. Cell 2004; 15: 3450), it remains a major challenge to understand later events in oncogene-induced signalling and, in particular, which regulated genes are important in the establishment of the transformed phenotype.

In order to investigate novel aspects of these pathways in cancer cells, especially those with activated RAS oncogenes, we have employed a functional genomics approach using post-transcriptional gene silencing by genome-scale libraries of RNA interference agents. Three main libraries have been used. One is a library of retroviral RNA interference vectors targeting 8000 different human genes, which has been generated by René Bernards at the Netherlands Cancer Institute in collaboration with Cancer Research UK (Berns et al., Nature 2004; 428: 431). Another is the Dharmacon genome wide library of small synthetic double stranded RNA oligonucleotides targeting the entire human genome. In addition, a commercial RNAi library targeting the entire Drosophila genome is also being used.

Two Screening Approaches
Two approaches to screening have been applied. In one, genes corresponding to a large fraction of the genome are systematically silenced one by one — in a high Nicke, Downard, Hancockthroughput format screen — allowing the identification of genes that are required for a particular aspect of the transformed phenotype to occur. The proteins they encode might make excellent targets for the development of novel therapeutic drugs. This has lead us to the identification of CUTL1 as a promoter of tumour cell invasiveness downstream of TGF beta (Michl et al. 2005, Cancer Cell 7, 521).

In the second approach — a selective screen using retroviral RNA interference vectors — many genes are silenced at the same time in a mixed pool of cells, with the screen being designed in such away that only cells acquiring the desired phenotype as a result of knock down of expression of one of these genes can survive.

These cells, along with the RNAi sequence they carry are then identified as they emerge at the end of the screen. This has lead to the identification of MINK as a critical mediator of Ras oncogene-induced senescence in ovarian epithelial cells (Nicke et al. 2005, Molecular Cell 20, 673). Both of these approaches utilised the NKI retroviral RNA interference library.
 

 Large-Scale Screening
The use of large-scale RNA interference libraries thus shows considerable promise in uncovering novel targets for cancer therapy. We are now using the genome-wide RNAi oligo library to study the regulation of several signaling systems within the cell. These include the control of the Akt and mTOR pathway, which is being analysed by measuring the effect of RNAi oligos on the phosphorylation state of several proteins in the pathway and also cell size, survival and proliferation. It is hoped that novel components might be identified in this key regulatory pathway that is central to cell survival, proliferation, metabolism and protein synthesis.

Another high throughput screen being carried out on a genome-wide scale studies the effect of knock down of expression of different genes on the sensitivity of Ras transformed cells to common chemotherapeutic agents. We hope that this will lead to the identification of genes that might be of diagnostic value in predicting the drug sensitivity or otherwise of a tumour, as well as pointing to potential therapeutic targets that might overcome resistance of tumours to existing drugs.

A third large-scale screen is searching for synthetic lethal interactions between gene silencing and the Ras oncogene, comparing a colon cancer cell line containing an activated KRAS allele with a normal derivative in which this has been deleted by homologous recombination. This might uncover proteins whose therapeutic targeting would be expected to provide a high differential toxicity towards tumour versus normal cells. A number of interesting leads are being actively pursued from each of these screens.

 

Contact Details

Julian Downward, PhD, FRS
Principal Scientist
Signal Transduction Laboratory
Cancer Research UK London Research Institute
44 Lincoln's Inn Fields, London WC2A 3PX, UK
Telephone +44 20 7269 3533
Fax +44 20 7269 3094
Email   
Group Members

David Hancock
Michael Steckel
Charles Swanton
Barbara Nicke
Olivier Pardo
Michela Marani

 

 

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Selected Publications
K. Lehmann, E. Janda, C. E. Pierreux, M. Rytömaa, A. Schulze, M. McMahon, C. S. Hill, H. Beug, J. Downward (2000) Genes & Development 14, 2610-2622. "Raf induces TGF secretion while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells."

A. Schulze, K. Lehmann, H. B. Jefferies, M. McMahon, J. Downward (2001) Genes & Development 15, 981-994. "Analysis of the transcriptional program induced by Raf in epithelial cells: implication of an EGF-like autocrine loop in protection from anoikis."

L. M. Martins, I. Iaccarino, T. Tenev, S. Gschmeissner, N. F. Totty, N. R. Lemoine, J. Savopoulos, C. W. Gray, C. L. Creasy, C. Dingwall and J. Downward (2002) J. Biol. Chem. 277, 439-444. "The Serine Protease Omi/HtrA2 Regulates Apoptosis by Binding XIAP through a Reaper-like Motif."

S. Basu, N. F. Totty, M.S. Irwin, M. Sudol, J. Downward (2003) Molecular Cell 11, 11-23. "Akt Phosphorylates the Yes-Associated Protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis."

J. Downward (2003) Nature Reviews Cancer 3, 11-22. "Targeting Ras signaling pathways in cancer therapy."

O.E. Pardo, A. Lesay, A. Arcaro, R. Lopes, B.L. Ng, P.H. Warne, I.A. McNeish, T.D. Tetley, N.R. Lemoine, H. Mehmet, M.J. Seckl, J. Downward (2003) Mol. Cell. Biol. 23, 7600-7610. "Fibroblast growth factor 2-mediated translational control of IAPs blocks mitochondrial release of Smac/DIABLO and apoptosis in small cell lung cancer cells."

J. Downward (2004) British Medical Journal 328, 1245-1248. "RNA interference."

J. Downward (2004) Oncogene 23, 8376-8383. "Use of RNA interference libraries to investigate oncogenic signalling in mammalian cells."

A. Schulze, B. Nicke, P.H. Warne, S. Tomlinson, J. Downward (2004) Mol. Biol. Cell 15, 3450-3463. "The transcriptional response to Raf activation is almost completely dependent on MEK activity and shows a major autocrine component."

L.M. Martins, A.Morrison, K. Klupsch, V. Fedele, N. Moisoi, P. Teismann, A. Abuin, E. Grau, M. Geppert, G.P. Livi, C.L. Creasy, A. Martin, I. Hargreaves, S.J. Heales, H. Okada, S. Brandner, J.B. Schulz, T. Mak, J. Downward (2004) Mol. Cell. Biol. 24, 9848-9862. "Neuroprotective role of the reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice."

S. Baksh, S. Tommasi, S. Fenton, V.C. Yu, L.M. Martins, G.P. Pfeifer, F. Latif, J. Downward, B.G. Neel (2005) Molecular Cell 18, 637-650. "The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death."

J. Downward (2005) Cell 121, 813-815. "RNA interference libraries prove their worth in hunt for tumor suppressor genes."

P. Michl, A.R. Ramjaun, O.E. Pardo, P.H. Warne, M. Wagner, R. Poulsom, C. D'Arrigo, K. Ryder, A. Menke, T. Gress, J. Downward (2005) Cancer Cell 7, 521-532. "CUTL1 is a target of TGF eta signaling that enhances cancer cell motility and invasiveness."

B. Nicke, J. Bastien, S.J. Khanna, P.H. Warne, V. Cowling, S.J. Cook, G. Peters, O. Delpuech, A. Schulze, K. Berns, J. Mullenders, R.L. Beijersbergen, R. Bernards, T.S. Ganesan, J. Downward (corresponding author), D.C. Hancock (2005) Molecular Cell 20, 673-685. "Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells."

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