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Signal Transduction and Apoptosis The Nobel Prize for Physiology or Medicine 2002 Sydney Brenner, John Sulston, and Robert Horvitz In a move that many will regard as long overdue, the Nobel committee honoured Sydney Brenner with the Nobel Prize for Physiology or Medicine. John Sulston and Robert Horvitz will share the prize that has been awarded in recognition of the triumvirate's seminal studies on the nematode worm Caenorhabditis elegans. Their discoveries concerning genetic regulation of organ development and programmed cell death have given insights into these processes in many other organisms. The 2001 Nobel Prize in Physiology or Medicine 8 October 2001 The Nobel Assembly at Karolinska Institutet has today decided to award The Nobel Prize in Physiology or Medicine for 2001 jointly to Leland H. Hartwell, R. Timothy (Tim) Hunt and Paul M. Nurse for their discoveries of "key regulators of the cell cycle" Summary All organisms consist of cells that multiply through cell division. An adult human being has approximately 100 000 billion cells, all originating from a single cell, the fertilized egg cell. In adults there is also an enormous number of continuously dividing cells replacing those dying. Before a cell can divide it has to grow in size, duplicate its chromosomes and separate the chromosomes for exact distribution between the two daughter cells. These different processes are coordinated in the cell cycle. This year's Nobel Laureates in Physiology or Medicine have made seminal discoveries concerning the control of the cell cycle. They have identified key molecules that regulate the cell cycle in all eukaryotic organisms, including yeasts, plants, animals and human. These fundamental discoveries have a great impact on all aspects of cell growth. Defects in cell cycle control may lead to the type of chromosome alterations seen in cancer cells. This may in the long term open new possibilities for cancer treatment. 君子務本 本立而道生 Cell Death Diseases associated with dysregulation of apoptosis Thompson CB. Science 267, 1456-1462 (1995) Agents reported to induce or inhibit apoptosis Hoechst 33258 stain of HeLa cells Starosporine Control EM (Left: condensed chromatin) (Right: cytoplasmic blebbing) Methods for DNA fragmentation analysis Gel electrophoresis C ST TUNEL assay C ST Fluorescence Terminal dUTP Nucleotide Labeling assay fluorecein-labeled deoxynucleotide/ terminal deoxynucleotidyl transferase enzyme (Staurosporine-treated A431 cells, 10 mM, 6 hr) Phosphatidylserine (PS) externalization Annexin V-FITC/PI stain (Staurosporine-treated A431 cells , 10 mM, 6 hr ) (PDT-treated A431 cells , 2 hr ) Caenorhabditis elegans Life cycle of Caenorhabditis elegans Identification of the genes involved in developmental apoptosis in C. elegans Cell 75, 641-652, Nov. 19, 1993 The C. elegans Cell Death Gene ced-3 Encodes a Protein Similar to Mammalian Interleukin-1b-Converting Enzyme Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. Program of Neurosciences, Harvard Medical School, Boston, Massachusetts 02115. We have cloned the C. elegans cell death gene ced-3. A ced-3 transcript is most abundant during embryogenesis, the stage during which most programmed cell deaths occur. The predicted CED-3 protein shows similarity to human and murine interleukin-1 beta-converting enzyme and to the product of the mouse nedd-2 gene, which is expressed in the embryonic brain. The sequences of 12 ced-3 mutations as well as the sequences of ced-3 genes from two related nematode species identify sites of potential functional importance. We propose that the CED-3 protein acts as a cysteine protease in the initiation of programmed cell death in C. elegans and that cysteine proteases also function in programmed cell death in mammals. Interleukin-1b-Converting Enzyme (ICE) Nature 356, 768-774 (1992) A novel heterodimeric cysteine protease is required for Interleukin-1b processing in monocytes THP-1 cells, the human monocytic leukemia cell line Organization of the human ICE cDNA Substrate specificity of the human ICE cDNA Comparison of structural features of the CED-3 protein and human ICE Nature 371, Sep. 22 (1994) Nature 376, 37-43 (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis Biotin-DEVD-CHO TIBS 22, 299-306 (1997) caspase cysteine aspartic acid Specificities and proposed biological functions for caspases Proteolytic substrates for caspases during apoptosis ? Cell 86, 147-157, (1996) Induction of Apoptotic Program in Cell-Free Extracts: Requirement for dATP and Cytochrome C Cell 90, 405-413, (1997) Apaf-1, a Human Protein Homologous to C. elegans CED-4, Participates in Cytochrome c-Dependent Activation of Caspase-3 Model of caspase-3 activation through mitochondria The wider Bcl-2 family Functional role of CED-9/CED-4/CED-3 complexes Model of receptor-mediated caspase activation Intrinsic cell death signaling Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 199– 214 Extrinsic cell death signaling Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 199– 214 TIBS 22, 299-306 (1997) Model of caspase-3 activation through mitochondria