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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