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CNC Research
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Cell Death
January 21 - 25
Armanda Santos

Auditório do IBILI - Pólo III

Course Sponsor: Biogen Idec

Jonathan Ham
Molecular Haematology and Cancer Biology Unit,
Camelia Botnar Laboratories
Institute of Child Health
University College London
London WC1N 1EH, UK

Michael J. Courtney
Dept. of Neurobiology
A. I. Virtanen Institute
University of Kuopio
Kuopio FIN 70211, Finland
Luis Miguel Martins
Cell Death Regulation Laboratory
MRC Toxicology Unit
Leicester LE1 9HN, UK

Armanda E. Santos
Center for Neuroscience and Cell Biology &
Faculty of Pharmacy
University of Coimbra
3004-517 Coimbra, Portugal


Monday, January 21
9h -10.15h: Introduction to apoptosis
Jonathan Ham
10.30h -11.45h: Introduction to mitochondria
Luís Miguel Martins

Tuesday, January 22
9h – 10.15h: Regulation of the cell death programme by signalling pathways
Jonathan Ham
10.30h – 11.45h: Stress-activated protein kinases in cell death
Michael Courtney
14h – 16h: Analysis and discussion of papers
Jonathan Ham
Note: Student presentations should not take more than 30 minutes per paper
Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 17: 393-403 (2005).
Students: Ana Sofia Cabral e João Costa
Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE, Ierino H, Lee EF, Fairlie WD, Bouillet P, Strasser A, Kluck RM, Adams JM, Huang DC. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315: 856-859 (2007).
Students: Ana Sofia Azevedo, Sara Figueiredo e Pedro Marques

Wednesday, January 23
9h – 10.15h: Transcriptional control of apoptosis
Jonathan Ham
10.30h – 11.45h: Mitochondrial stress pathways and cell death / Seminar

Luis Miguel Martins
14h – 16h: Analysis and discussion of papers
Luís Miguel Martins
Note: Student presentations should not take more than 30 minutes per paper
Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, and Larsson NG. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417-23 (2004).
Students: Filipe Leal, Lígia Silva e Filipe Duarte
Zhao Q, Wang J, Levichkin IV, Stasinopoulos S, Ryan MT and Hoogenraad. A mitochondrial specific stress response in mammalian cells. EMBO J. 21: 4411-9 (2002).
Students: Joana Marinho e Filomena Silva
Kamata H, Honda S, Maeda S, Chang L., Hirata H and Karin M. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120: 649-61 (2005).
Students: Marta Vieira e Sueli Marques
Dai, C., Whitesell, L., Rogers, A.B. & Lindquist, S.L. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130: 1005-18 (2007).
Solimini, N.L., Luo, J. & Elledge, S.J. Non-oncogene addiction and the stress phenotype of cancer cells. Cell 130: 986-8 (2007).
Students: Gil Cunha, Susana Louros e Tiago Capote

Thursday, January 24
9h -10.15h: Mechanisms of glutamate receptor mediated excitotoxic neuronal death I: Calpains, AIF and Ca2+-permeable AMPA receptor-mediated excitotoxicity
Armanda Santos
10.30h – 11.45h: Mechanisms of glutamate receptor mediated excitotoxic neuronal death II: NMDA receptors and associated proteins in excitotoxicity
Michael Courtney
14h – 16h: Analysis and discussion of papers
Michael Courtney

Note: Student presentations should not take more than 30 minutes per paper
The first two papers are highly related, thus it is convenient that students take a look on both. A third paper is included as extra-information.
Cui H, Hayashi A, Sun HS, Belmares MP, Cobey C, Phan T, Schweizer J, Salter MW, Wang YT, Tasker RA, Garman D, Rabinowitz J, Lu PS, Tymianski M. PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors. J Neurosci 27: 9901-9915 (2007).
Students presenting: João Santos, Nélio Gonçalves e Graciano Leal
Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, Wang YT, Salter MW, Tymianski M. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science 298: 846-850 (2002).
Students presenting: Joana Ferreira e Manuel Barroso
Kim MJ, Futai K, Jo J, Hayashi Y, Cho K, Sheng M. Synaptic Accumulation of PSD-95 and Synaptic Function Regulated by Phosphorylation of Serine-295 of PSD-95. Neuron. 56:488-502 (2007).

Friday, January 25
14h – 15:15h: New perspectives in targeting excitotoxicity / Seminar
Michael Courtney
16h: CNC seminar“The role of AP-1 transcription factors and their target genes in developmental neuronal death”
Jonathan Ham


Danial NN & Korsmeyer SJ. (2004)
Cell death: critical control points. Cell 116: 205-219. Review.

Kim H, Rafiuddin-Shah M, Tu HC, Jeffers JR, Zambetti GP, Hsieh JJ, and Cheng EH. (2006)
Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol. 8: 1348-1358.

Willis SN & Adams JM. (2005)
Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol. 17: 617-625. Review.

Hengartner MO. (2000)
The biochemistry of apoptosis. Nature 407: 770-776. Review.

Thellmann M, Hatzold J and Conradt B. (2003)
The Snail-like CES-1 protein of C. elegans can block the expression of the BH3-only cell-death activator gene egl-1 by antagonizing the function of bHLH proteins. Development 130: 4057-4071.
Whitfield, J., Neame, S.J., Paquet, L., Bernard, O. and Ham, J. (2001)
Dominant negative c-Jun promotes neuronal survival by reducing Bim expression and inhibiting mitochondrial cytochrome c release.  Neuron 29, 629-643.
Gilley, J., Coffer, P. and Ham, J. (2003)
FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. Journal of Cell Biology 162, 613-622.

Ham, J., Towers, E., Gilley, J., Terzano, S. and Randall, R.A. (2005)
BH3-only proteins:  key regulators of neuronal apoptosis.  Cell Death and Differentiation 12, 1015-1020.
Kwak S & Weiss JH. (2006)
Calcium-permeable AMPA channels in neurodegenerative disease and ischemia.Curr Op Neurobiol 16: 281-287
Santos AE, Duarte CB, Iizuka M, Barsoumian EL, Ham J, Lopes MC, Carvalho AP, and Carvalho AL. (2006)
Excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors involves the AP-1 transcription factor.Cell Death Differ 13:652-60

Borsello T, Clarke PG, Hirt L, Vercelli A, Repici M, Schorderet DF, Bogousslavsky J, Bonny C (2003)
A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med. 9:1180-6.
Cao J, Semenova MM, Solovyan VT, Han J, Coffey ET, Courtney MJ (2004)
Distinct requirements for p38alpha and c-Jun N-terminal kinase stress-activated protein kinases in different forms of apoptotic neuronal death. J Biol Chem. 279:35903-13.
Wang LH, Besirli CG, Johnson EM Jr (2004)
Mixed-lineage kinases: a target for the prevention of neurodegeneration. Annu Rev Pharmacol Toxicol. 44:451-74.
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