The Nobel Prize in Physiology or Medicine 2001

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The Nobel Prize in Physiology or Medicine 2001
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Dr.Leland H. Hartwell

• Born October 30, 1939
• Fred Hutchinson Cancer Research Center, Seattle,
  WA, USA.

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Academic Education and Appointments

•  1961 B.S. California Institute of Technology
• 1964 Ph.D. Massachusetts Institute of Technology
• 1965-68 Associate Professor, University of
  California

• 1968- Associate Full Professor, University of
  Washington
• 1997 President and Director, Fred Hutchinson
  Cancer Research Center

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Selected Honours and Awards

• 1987 Member of the US National Academy of
  Sciences
• 1991 General Motors Sloan Award
• 1992 Gairdner Foundation International Award

• 1994 Genetics Society of America Medal
• 1998 The Albert Lasker Basic Medical Research
  Award

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DISCOVERIES

• CDC-genes (cell division cycle genes).
• CDC28, controls the first step in the
  progression through the G1-phase of the cell
  cycle, and was therefore also called "start".
• Checkpoints

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Saccharomyces cerevisiae
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Experiments

• Isolation of yeast cells in which genes
  controlling the cell cycle were altered (mutated)
  , using restrictive temperature (36ºC)
• using photo microscopy for analyzing the S.
  cerevisiae cell cycle

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Figure 5.Normal cells and cdc mutant cells
several hours after incubation at the restrictive
temperature.(A) wild type, (B) cdc8 (C) cdc24
(D) cdc10.
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CDC-genes

• cell division cycle genes
• CDC28, controls the first step in the
  progression through the G1-phase of the cell
  cycle, and was therefore also called "start" and
  its expression is a crucial point at which cell
  proliferation is integrated with extra- and
  intracellular signals

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CHECKPOINTS

• Checkpoints are control points at which
  regulatory proteins halt the cell cycle upon
  detecting damage to DNA, or other abnormalities,
  allowing repair before the cycle resumes. In
  their absence, cells would be prone to genetic
  damage.
• Many forms of cancer have since been linked to
  problems with checkpoint control

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Time-lapse photo microscopy of cells irradiated
with X-rays. Wild type cells at the timeof
irradiation (A) and several hours later (B). Note
that the originally unbudded G1 (A) cells
haveremained arrested as large budded cells (B)
while the budded G2 cell (A) has resumed cell
division(B). G1 haploid cells are very
inefficient at repairing double strand breaks
because of thelack of a template for homologous
recombinational repair.
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(Sir)Dr.Paul M.Nurse,

• born January 25,1949
• Imperial Research Cancer Fundation, London, UK.

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Academic Education and Appointments

• 1970 B.S., University of Birmingham
• 1973 Ph.D., University of East Anglia
• 1996- Director-General, Imperial Cancer Research
  Fund, London, Head of Cell Cycle Laboratory

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Selected Honours and Awards

• 1989 Fellow of the Royal Society
• 1992 Gairdner Foundation International Award
  (Canada)
• 1995 Foreign Associate of the US National Academy
  of Sciences

• 1997 General Motors Cancer Research Foundation
  Alfred P Sloan Jr Prize Medal (USA)
• 1998 Albert Lasker Award (USA)

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Schizosaccharomyces pombe
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DISCOVERIES

• cdc2
• CDK1
• The same gene controlled cell division in yeast
  and humans and hence everything in between(cell
  cycle control was conserved through evolution)

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CDC28cdc2

• two genes could substitute for one another
• both proteins acted in each organism at G1 and G2

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Under rapid growth conditions

• the G1 activation of CDC28 in S. cerevisiae is
  dependent on cell growth  

• the G2 activation of cdc2 in S. pombe is
  dependent on cell growth.

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Further roles of CDK

• CDKs are a part of the checkpoint control
• ensuring that mitosis only takes place when the
  genome is fully replicated.
• ensuring that there is only one S-phase in each
  cell cycle.

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Dr.R. Timothy Hunt

• born February 19,1943
• Imperial Research Cancer Fundation, UK.

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Academic Education and Appointments

• 1964 B.A. University of Cambridge
• 1968 Ph.D. University of Cambridge
• 1991- Principal Scientist, ICRF Clare Hall
  Laboratories

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Selected Honours and Awards

• 1991 Fellow of the Royal Society
• 1991 Foreign Associate of the US National Academy
  of Sciences
• 1993 Abraham White Scientific Achievement Award
  of the George Washington University

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sea urchin, Arbacia
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DISCOVERY

• Cyclins
• that regulate the CDK activity and select the
  target proteins to be phosphorylated

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CYCLINS

• Cyclins are proteins formed and degraded during
  each cell cycle. Periodic protein degradation is
  an important control mechanism of the cell cycle.
  (D cell division.)

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• The fundamental molecular mechanisms controlling
  the cell cycle are highly conserved through
  evolution and operate in the same manner in
  yeasts, insects, plants, animals and humans.

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CDK and cyclin together form an enzyme
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Control of cell cycle in animal cells
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MPF

• Maturation promoting factor( M-phase promoting
  factor)
• Controls entry into meiosisI and meiosis II
• MPF activity plays a role in developing oocytes
  in vertebrates.

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Checkpointsquality control of cell cycle

• S phase checkpoints
• DNA damage checkpoints
• Spindle checkpoints
• e.g.p53

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Why are their discoveries significant?

• It is thought that defective cell cycle control
  may cause genetic material to be inadequately
  passed from the parent cell to the two new
  daughter cells.
• These alterations to the chromosomes, in which
  parts are lost or rearranged, is likely to be
  important in the development of cancer cells.
• Increased levels of CDK molecules and cyclins
  have been found in some human tumours, such as
  breast cancer.
• It is possible that too much CDK in a cells may
  disrupt the cell cycle, and potentially cause
  these problems.
• In this case, treatments which inhibit the
  working of CDK molecules may have some promise as
  anti-cancer therapies.

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• The figure shows three pairs of chromosomes (1, 3
  and 14) in normal cells (left), compared with the
  same pairs in cancer cells (right). In cancer
  cells, the chromosome number may be altered
  (aneuploidy) and parts of chromosomes may be
  rearranged (visualized by different colours).
•    

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http//www.nobel.se/medicine/educational/2001/inde
x.html
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Figure 7. Electron microscopic image of the yeast
nucleus revealing the electron dense spindle pole
bodies imbedded in the nuclear membrane with
microtubules emanating from them.