Selected Publications

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

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

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

Schulze A, Lehmann K, Jefferies HBJ, McMahon M and Downward J. Analysis of the transcriptional program induced by Raf in epithelial cells. Genes Dev 2001; 15: 981-994. PubMed Full text

Lehmann K, Janda E, Pierreux CE, Rytomaa M, Schulze A, McMahon M, Hill CS, Beug H and Downward J. Raf induces TGFβ production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev 2000; 14: 2610-2622. PubMed Full text

Primary Research Publications

2009

Moisoi N, Klupsch K, Fedele V, East P, Sharma S, Renton A, Plun-Favreau H, Edwards RE, Teismann P, Esposti MD, Morrison AD, Wood NW, Downward J, Martins LM. Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. Cell Death Differ. 2009 Mar;16(3):449-64.

Cully M, Downward J. Translational responses to growth factors and stress. Biochem Soc Trans. 2009 Feb;37(Pt 1):284-8.

Downward J, Hahn WC. Genetic and cellular mechanisms of oncogenesis. Curr Opin Genet Dev. 2009 Feb;19(1):1-3.

Tain LS, Chowdhury RB, Tao RN, Plun-Favreau H, Moisoi N, Martins LM, Downward J, Whitworth AJ, Tapon N. Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin. Cell Death Differ. 2009 Mar 13.

Gandhi S, Wood-Kaczmar A, Yao Z, Plun-Favreau H, Deas E, Klupsch K, Downward J, Latchman DS, Tabrizi SJ, Wood NW, Duchen MR, Abramov AY. PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell. 2009 Mar 13;33(5):627-38

Liu ML, Liu MJ, Shen YF, Ryu H, Kim HJ, Klupsch K, Downward J, Hong ST. Omi is a mammalian heat-shock protein that selectively binds and detoxifies oligomeric amyloid-{beta}. J Cell Sci. 2009 Jun 1;122(Pt 11):1917-26

Swanton C, Nicke B, Schuett M, Eklund AC, Ng C, Li Q, Hardcastle T, Lee A, Roy R, East P, Kschischo M, Endesfelder D, Wylie P, Kim SN, Chen JG, Howell M, Ried T, Habermann JK, Auer G, Brenton JD, Szallasi Z, Downward J. Chromosomal instability determines taxane response. Proc Natl Acad Sci U S A. 2009 May 26;106(21):8671-6.

2008

Cross JR, Postigo A, Blight K, Downward J. Viral pro-survival proteins block separate stages in Bax activation but changes in mitochondrial ultrastructure still occur. Cell Death Differ 2008;15(6):997-1008

Kawamoto Y, Kobayashi Y, Suzuki Y, Inoue H,Tomimoto H, Akiguchi I, Budka H, Martins LM, Downward J, Takahashi R. Accumulation of HtrA2/Omi in neuronal and glial inclusions in brains with alpha-synucleinopathies. J Neuropathol Exp Neurol 2008;67(10):984-93

Lee A, East P, Pepper S, Nicke B, Szallasi Z, Eklund A, Downward J and Swanton C. Concordance of exon array and real-time PCR assessment of gene expression following cancer cell cytotoxic drug exposure. Cell Cycle 2008;7(24): 7891

Moisoi N, Klupsch K, Fedele V, East P, Sharma S, Renton A, Plun-Favreau H, Edwards RE, Teismann P, Esposti MD, Morrison AD, Wood NW, Downward J, Martins LM. Mitochondrial dysfunction triggered by loss of HtrA2 results n the activation of a brain-specific transcriptional stress response. Cell Death and Differentiation 2008; doi:10.1038/cdd.2008.166

Swanton C, Szallasi Z, Brenton JD, Downward J. Functional genomic analysis of drug sensitivity pathways to guide adjuvant strategies in breast cancer. Breast Cancer Res 2008;10(5):214

Wood-Kaczmar A, Gandhi S, Yao Z, Abramov AS, Miljan EA, Keen G, Stanyer L, Hargreaves I, Klupsch K, Deas E, Downward J, Mansfield L, Jat P,Taylor J, Heales S, Duchen MR, Latchman D,Tabrizi SJ,Wood NW. PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE 2008;3(6):e2455

2007

Ahmed AA, Mills AD, Ibrahim AEK, Temple J, Blenkiron C, Vias M, Massie CE, Iyer NG, McGeoch A, Crawford R, Nicke B, Downward J, Swanton C, Bell SD, Earl HM, Laskey RA, Caldas C, Brenton JD. The extracellular matrix protein TGFBI induces microtubule stabilization and sensitizes ovarian cancers to paclitaxel. Cancer Cell 2007; 12(6):514-527

Calleja V, Alcor D, Laguerre M, Park J, Vojnovic B, Hemmings BA, Downward J, Parker PJ, Larijani B. Intramolecular and intermolecular interactions of protein kinase B define its activation in vivo. PLoS Biol 2007; 5(4):780-791

Delpuech O, Griffiths B, East P, Essafi A, Lam EWF, Burgering B, Downward J, Schulze A. Induction of Mxi1-SR alpha by FOXO3a contributes to repression of Myc-dependent gene expression. Mol Cell Biol 2007; 27(13):4917-4930

Gupta S, Ramjaun AR, Haiko P, Wang YH, Warne PH, Nicke B, Nye E, Stamp G, Alitalo K, Downward J. Binding of Ras to phosphoinositide 3-kinase p110 alpha is required for Ras-driven tumorigenesis in mice. Cell 2007; 129(5):957-968

Leal-Sanchez J, Couzinet A, Rossin A, Abdel-Sater F, Chakrabandhu K, Luci C, Anjuere F, Stebe E, Hancock D, Hueber A-O. Requirement for Daxx in mature T-cell proliferation and activation. Cell Death Differ 2007; 14(4):795-806

Plun-Favreau H, Klupsch K, Moisoi N, Gandhi S, Kjaer S, Frith D, Harvey K, Deas E, Harvey RJ, McDonald N, Wood NW, Martins LM, Downward J. The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nat Cell Biol 2007; 9(11):1243-1252

Ramjaun AR, Downward J. Ras and phosphoinositide 3-kinase - Partners in development and tumorigenesis. Cell Cycle 2007; 6(23):2902-2905

Ramjaun AR, Tomlinson S, Eddaoudi A, Downward J. Upregulation of two BH3-only proteins, Bmf and Bim, during TGF beta-induced apoptosis. Oncogene 2007; 26(7):970-981

Ripka S, Konig A, Buchholz M, Wagner M, Sipos B, Kloppel G, Downward J, Gress TM, Michl P. WNT5A - target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer. Carcinogenesis 2007; 28(6):1178-1187

Swanton C, Marani M, Pardo O, Warne PH, Kelly G, Sahai E, Elustondo F, Chang J, Temple J, Ahmed AA, Brenton JD, Downward J, Nicke B. Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs. Cancer Cell 2007; 11(6):498-512

Swanton C, Nicke B, Marani M, Kelly G, Downward J. Initiation of high frequency multi-drug resistance following kinase targeting by siRNAs. Cell Cycle 2007; 6(16):2001-2004

Wells V, Downward J, Mallucci L. Functional inhibition of PI3K by the beta GBP molecule suppresses Ras-MAPK signalling to block cell proliferation. Oncogene 2007; 26(55):7709-7714

2006

Cully M, You H, Levine AJ, Mak TW. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006; 6:184-192

Janda E, Nevolo M, Lehmann K, Downward J, Beug H, Grieco M. Raf plus TGF beta-dependent EMT is initiated by endocytosis and lysosomal degradation of E-cadherin. Oncogene 2006; 25(54):7117-7130

Jansson AL, Yasmin L, Warne P, Downward J, Palmer RH, Hallberg B. Exoenzyme S of Pseudomonas aeruginosa is not able to induce apoptosis when cells express activated proteins, such as Ras or protein kinase B/Akt. Cell Microbiol 2006; 8(5):815-822

Katso RM, Pardo OE, Palamidessi A, Franz CM, Marinov M, De Laurentiis A, Downward J, Scita G, Ridley AJ, Waterfield MD, Arcaro A. Phosphoinositide 3-kinase C2 beta regulates cytoskeletal organization and cell migration via Rac-dependent mechanism. Mol Biol Cell 2006; 17(9):3729-3744

Khanzada UK, Pardo OE, Meier C, Downward J, Seckl MJ, Arcaro A. Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling. Oncogene 2006; 25(6):877-887

Klupsch K, Downward J. The protease inhibitor Ucf-101 induces cellular responses independently of its known target, HtrA2/Omi. Cell Death Differ 2006; 13(12):2157-2159

Michl P, Knobel B, Downward J. CUTL1 is phosphorylated by protein kinase A, modulating its effects on cell proliferation and motility. J Biol Chem 2006; 281(22):15138-15144

Pardo OE, Wellbrock C, Khanzada UK, Aubert M, Arozarena I, Davidson S, Bowen F, Parker PJ, Filonenko VV, Gout IT, Sebire N, Marais R, Downward J, Seckl MJ. FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKC epsilon, B-Raf and S6K2. EMBO J 2006; 25(13):3078-3088

Postigo A, Cross JR, Downward J, Way M. Interaction of F1L with the BH3 domain of Bak is responsible for inhibiting vaccinia-induced apoptosis. Cell Death Differ 2006; 13(10):1651-1662

Shin SY, Bahk YY, Ko J, Chung I-Y, Lee YS, Downward J, Eibel H, Sharma PM, Olefsky JM, Kim Y-H, Lee B, Lee YH. Suppression of Egr-1 transcription through targeting of the serum response factor by oncogenic H-Ras. EMBO J 2006; 25(5):1093-1103

2005

Baksh S, Tommasi S, Fenton S, Yu VC, Martins LM, Pfeifer GP, Latif F, Downward J, Neel BG. The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to bax conformational change and cell death. Mol Cell 2005; 18(6):637-650

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 TGF beta signaling that enhances cancer cell motility and invasiveness. Cancer Cell 2005; 7(6):521-532

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. Mol Cell 2005; 20(5):673-685

Porstmann T, Griffiths B, Chung Y-L, Delpuech O, Griffiths JR, Downward J, Schulze A. PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene 2005; 24(43):6465-6481

Raoul C, Barthelemy C, Couzinet A, Hancock D, Pettmann B, Hueber A-O. Expression of a dominant negative form of Daxx in vivo rescues motoneurons from fas (CD95)-induced cell death. J Neurobiol 2005; 62(2):178-188

Stoll V, Calleja V, Vassaux G, Downward J, Lemoine NR. Dominant negative inhibitors of signalling through the phosphoinositol 3-kinase pathway for gene therapy of pancreatic cancer. Gut 2005; 54(1):109-116

Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, Gasser T, Wszolek Z, Muller T, Bornemann A, Wolburg H, Downward J, Riess O, Schulz JB, Kruger R. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet 2005; 14(15):2099-2111

2004

Dallol A, Agathanggelou A, Fenton SL, Ahmed-Choudhury J, Hesson L, Vos MD, Clark GJ, Downward J, Maher ER, Latif F. RASSFIA interacts with microtubule-associated proteins and modulates microtubule dynamics. Cancer Res 2004; 64(12):4112-4116

Fenton SL, Dallol A, Agathanggelou A, Hesson L, Ahmed-Choudhury J, Baksh S, Sardet C, Dammann R, Minna JD, Downward J, Maher ER, Latif F. Identification of the E1A-regulated transcription factor p120(E4F) as an interacting partner of the RASSF1A candidate tumor suppressor gene. Cancer Res 2004; 64(1):102-107

Lima RT, Martins LM, Guimaraes JE, Sambade C, Vasconcelos MH. Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells. Cancer Gene Ther 2004; 11(5):309-316

Marani M, Hancock D, Lopes R, Tenev T, Downward J, Lemoine NR. Role of Bim in the survival pathway induced by Raf in epithelial cells. Oncogene 2004; 23(14):2431-2441

Martins LM, Morrison A, Klupsch K, Fedele V, Moisoi N, Teismann P, Abuin A, Grau E, Geppert M, Livi GP, Creasy CL, Martin A, Hargreaves L, Heales SJ, Okada H, Brandner S, Schulz JB, Mak T, Downward J. Neuroprotective role of the reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol Cell Biol 2004; 24(22):9848-9862

Schulze A, Nicke B, Warne PH, Tomlinson S, Downward J. The transcriptional response to Raf activation is almost completely dependent on mitogen-activated protein kinase kinase activity and shows a major autocrine component. Mol Biol Cell 2004; 15(7):3450-3463

Vyas S, Juin P, Hancock D, Suzuki Y, Takahashi R, Triller A, Evan G. Differentiation-dependent sensitivity to apoptogenic factors in PC12 cells. J Biol Chem 2004; 279(30):30983-30993

2003

Agathanggelou A, Bieche I, Ahmed-Choudhury J, Nicke B, Dammann R, Baksh S, Gao B, Minna JD, Downward J, Maher ER, Latif F. Identification of novel gene expression targets for the Ras association domain family 1 (RASSF1A) tumor suppressor gene in non-small cell lung cancer and neuroblastoma. Cancer Res 2003; 63(17):5344-5351

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. Mol Cell 2003; 11(1):11-23

Calleja V, Ameer-Beg SM, Vojnovic B, Woscholski R, Downward J, Larijani B. Monitoring conformational changes of proteins in cells by fluorescence lifetime imaging microscopy. Biochem J 2003; 372(Pt 1):33-40

Iaccarino I, Hancock D, Evan G, Downward J. c-Myc induces cytochrome c release in Rat1 fibroblasts by increasing outer mitochondrial membrane permeability in a Bid-dependent manner. Cell Death Differ 2003; 10(5):599-608

Khanna S, Warnasuriya GD, Downward J, Naaby-Hansen S. RNAi and 2DE, a promising combination for analysis of phospho-signalling and substrate identification. Lett Pept Sci 2003; 10(5-6):437-445

Martins LM, Turk BE, Cowling V, Borg A, Jarrell ET, Cantley LC, Downward J. Binding specificity and regulation of the serine protease and PDZ domains of HtrA2/Omi. J Biol Chem 2003; 278(49):49417-49427

Nicolas FJ, Lehmann K, Warne PH, Hill CS, Downward J. Epithelial to mesenchymal transition in Madin-Darby canine kidney cells is accompanied by down-regulation of Smad3 expression, leading to resistance to transforming growth factor-beta-induced growth arrest. J Biol Chem 2003; 278(5):3251-3256

Pardo OE, Lesay A, Arcaro A, Lopes R, Ng BL, Warne PH, McNeish IA, Tetley TD, Lemoine NR, Mehmet H, Seckl MJ, Downward J. Fibroblast growth factor 2-mediated translational control of IAPs blocks mitochondrial release of Smac/DIABLO and apoptosis in small cell lung cancer cells. Mol Cell Biol 2003; 23(21):7600-7610

Tamas P, Solti Z, Bauer P, Illes A, Sipeki S, Bauer A, Farago A, Downward J, Buday L. Mechanism of epidermal growth factor regulation of Vav2, a guanine nucleotide exchange factor for Rac. J Biol Chem 2003; 278(7):5163-5171

2002

Cowling V, Downward J. Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway: absolute requirement for removal of caspase-6 prodomain. Cell Death Differ 2002; 9(10):1046-1056

Edme N, Downward J, Thiery J-P, Boyer B. Ras induces NBT-II epithelial cell scattering through the coordinate activities of Rac and MAPK pathways. J Cell Sci 2002; 115(12):2591-2601

Inabe K, Ishiai M, Scharenberg AM, Freshney N, Downward J, Kurosaki T. Vav3 modulates B cell receptor responses by regulating phosphoinositide 3-kinase activation. J Exp Med 2002; 195(2):189-200

Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H, Grunert S. Ras and TGF beta cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 2002; 156(2):299-313

Janda E, Litos G, Grunert S, Downward J, Beug H. Oncogenic Ras/Her-2 mediate hyperproliferation of polarized epithelial cells in 3D cultures and rapid tumor growth via the PI3K pathway. Oncogene 2002; 21(33):5148-5159

Marani M, Tenev T, Hancock D, Downward J, Lemoine NR. Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol 2002; 22(11):3577-3589

Martins LM, Iaccarino I, Tenev T, Gschmeissner S, Totty NF, Lemoine NR, Savopoulos J, Gray CW, Creasy CL, Dingwall C, Downward J. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J Biol Chem 2002; 277(1):439-444

Pardo OE, Arcaro A, Salerno G, Raguz S, Downward J, Seckl MJ. Fibroblast growth factor-2 induces translational regulation of Bcl-X-L and Bcl-2 via a MEK-dependent pathway: correlation with resistance to etoposide-induced apoptosis. J Biol Chem 2002; 277(14):12040-12046

Reynolds LF, Smyth LA, Norton T, Freshney N, Downward J, Kioussis D, Tybulewicz VLJ. Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma 1 via phosphoinositide 3-kinase-dependent and -independent pathways. J Exp Med 2002; 195(9):1103-1114

Vyas S, Bechade C, Riveau B, Downward J, Triller A. Involvement of survival motor neuron (SMN) protein in cell death. Hum Mol Genet 2002; 11(22):2751-2764

Other Publications

Buday L, Downward J. Many faces of Ras activation. Biochim Biophys Acta 2008;1775(2):263-73

Cully M, Downward J. SnapShot: Ras Signaling. Cell 2008;133(7):1292-1292

Downward J, Basu S. YAP and p73: a complex affair. Mol Cell 2008;32(6):749-50

Downward J. Targeting RAS and PI3K in lung cancer. Nat Med 2008;14(12):1315-6

Swanton C, Downward J. Unraveling the complexity of endocrine resistance in breast cancer by functional genomics Cancer Cell 2008;13(2):83-5

Buday L, Downward J. Roles of cortactin in tumor pathogenesis. Biochim Biophys Acta [Rev Cancer] 2007; 1775(2):263-273

Downward J. Prelude to an anniversary for the RAS oncogene. Science 2006; 314(5798):433-434

Downward J. Signatures guide drug choice. Nature 2006; 439(7074):274-275

Echeverri CJ, Beachy PA, Baum B, Boutros M, Buchholz F, Chanda SK, Downward J, Ellenberg J, Fraser AG, Hacohen N, Hahn WC, Jackson AL, Kiger A, Linsley PS, Lum L, Ma Y, Mathey-Prevot B, Root DE, Sabatini DM, Taipale J, Perrimon N, Bernards R. Minimizing the risk of reporting false positives in large-scale RNAi screens. Nat Methods 2006; 3(10):777-779

Michl P, Downward J. CUTL1: a key mediator of TGF beta-induced tumor invasion. Cell Cycle 2006; 5(2):132-134

Swanton C, Tomlinson I, Downward J. Chromosomal instability, colorectal cancer and taxane resistance. Cell Cycle 2006; 5(8):818-823

Downward J. RNA interference libraries prove their worth in hunt for tumor suppressor genes. Cell 2005; 121(6):813-815

Michl P, Downward J. Mechanisms of disease: PI3K/AKT signaling in gastrointestinal cancers. Z Gastroenterol 2005; 43(10):1133-1139

Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol 2004; 15(2):177-182

Downward J. RNA interference-based functional genomics in cancer research: an introduction. Oncogene 2004; 23(51):8334-8335

Downward J. Science, medicine, and the future: RNA interference. BMJ 2004; 328(7450):1245-1248

Downward J. Use of RNA interference libraries to investigate oncogenic signalling in mammalian cells. Oncogene 2004; 23(51):8376-8383

Swanton C, Nicke B, Downward J. RNA interference, DNA methylation, and gene silencing: a bright future for cancer therapy? Lancet Oncol 2004; 5(11):653-654

Downward J. Cell biology: metabolism meets death. Nature 2003; 424(6951):896-897

Downward J. Targeting ras signalling pathways in cancer therapy. Nat Rev Cancer 2003; 3(1):11-22

Downward J, Goff SP. Update on The Big C: complexity and cross-talk between pathways. Curr Opin Genet Dev 2002; 12(1):11-13

Martins LM. The serine protease Omi/HtrA2: a second mammalian protein with a Reaper-like function. Cell Death Differ 2002; 9(7):699-701