Julian Downward

Oncogene Biology Laboratory

Our interests include the mechanisms by which cells respond to external signals that regulate their proliferation and survival, in particular the signalling pathways along which information is transferred leading from cell surface receptors to events in the cell nucleus, and how these are altered during the process of malignant transformation. We have characterised the molecular details of how Ras oncoproteins, which are mutationally activated in 30 per cent of human tumours, are regulated and how they transmit their signal to the cell through direct binding to multiple effector proteins including Raf and phosphatidylinositol 3-kinase.

We are using whole genome scale RNA interference libraries to identify new components of critical growth regulatory pathways. In addition we are screening for genes that are required for the survival of Ras transformed, but not normal, cells and also for genes that when disrupted may restore the sensitivity of drug resistant tumour cells to established chemotherapeutic agents.

Selected publications

Fritsch R, de Krijger I, Fritsch K, George R, Reason B, Kumar MS, Diefenbacher M, Stamp G, Downward J.
RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms. Cell. 2013;153(5):1050-63 (Abstract)

Molina-Arcas M, Hancock DC, Sheridan C, Kumar MS, Downward J. Coordinate Direct Input of Both KRAS and IGF1 Receptor to Activation of PI3 kinase in KRAS-Mutant Lung Cancer. Cancer Discov. 2013;3(5):548-63 (Abstract)

Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883-92 (Abstract)

Kumar S, Hancock D, Molina-Arcas M, Steckel M, East P, Diefenbacher M, Armenteros-Monterroso E, Lassailly F, Matthews N, Nye E, Stamp G, Behrens A, Downward J. The GATA2-driven oncogene network is requisite for RAS oncogene-driven no-small cell lung cancer. Cell 2012;149(3):642-55 (Abstract)

Steckel M, Molina-Arcas M, Weigelt B, Marani M, Warne PH, Kuznetsov H, Kelly G, Saunders B, Howell M, Downward J, Hancock DC. Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies. Cell Res. 2012;22(8):1227-45 (Abstract)

Michl P, Ramjaun AR, Pardo OE, Warne PH, Wagner M, Poulsom R, D'Arrigo C, Ryder K, Menke A, Gress T, Downward J. CUTL1 is a target of TGFb signaling that enhances cancer cell motility and invasiveness. Cancer Cell. 2005;7:521-532 (Abstract)

Nicke B, Bastien J, Khanna SJ, Warne PH, Cowling V, Cook SJ, Peters G, Delpuech O, Schulze A, Berns K, Mullenders J, Beijersbergen RL, Bernards R, Ganesan TS, Downward J, Hancock DC. Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells. Molecular Cell. 2005;20:673-685 (Abstract)

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

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

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

Julian Downward

julian.downward@crick.ac.uk
+44 (0)20 379 61838

  • Qualifications and history
  • 1986 PhD in Natural Sciences, Imperial College, London University, UK
  • 1986 Postdoctoral Research Fellow, Massachusetts Institute of Technology, USA
  • 1989 Established lab at the Imperial Cancer Research Fund (in 2002 the Imperial Cancer Research Fund became Cancer Research UK)
  • 2015 Associate Research Director, the Francis Crick Institute, London, UK