The Cell Cycle

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The Cell Cycle

• Elisabeth Bock
• Protein Laboratory
• Department of Neuroscience and Pharmacology
• http//www.plab.ku.dk/bock/index.htm
• Link The Cell Cycle

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Litterature

• Chapter 4 Cellular Reproduction
  Multiplication by division in
  Inside the Cell, NIH
• Chapter 16 The Cell Cycle
• in Cooper Hausman The Cell

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Overview of lectures

• The cell cycle is divided into 4 phases
• A control system regulates the progress through
  the cycle
• The control system depends on cyclically
  activated protein kinases in the cell composed of
  a cyclin and a cyclin-dependent protein kinase
  (Cdk)
• Extracellular factors are also required for
  growth, division and survival
• Mitosis and cytokinesis
• Meiosis

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The cell doctrine

• A cell arises from a previous cell which
  duplicates
• its content and divides The cell cycle
• How does a cell duplicate its content?
• How does it partition the duplicated content and
  split it in two?
• How are these processes regulated?

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The 4 phases of the cell cycle
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The cell cycle control system

• A central regulatory system coordinates the
  activities and thereby ensures correct
  progression
• The system depends on cyclically activated
  protein kinases

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Regulation of protein function

• Protein function can be switched on and off by
  adding or removing phosphate groups to a protein
• Kinases are enzymes that transfer a phosphate
  group from ATP to a sidechain of an aminoacid on
  a target protein
• The phosphate group is removed by protein
  phosphatases

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Cyclins and Cdks

• Cell cycle regulating kinases are controlled by
  cyclins
• Cyclins have no enzymatic activity
• Cyclins have to bind to the kinases before the
  kinases can become active
• The kinases are therefore called
  cyclin-dependent protein kinases or Cdks

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Regulation of Cdk activity I

• Cyclins are accumulated and destroyed during the
  cell cycle
• Regulation of cyclin concentration controls Cdk
  activity
• Cdk concentration does not change during the
  cycle

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Cyclin degradation

• Ubiquitin molecules are covalently attached to
  cyclin
• Ubiquitinated-cyclin is targeted for proteasomes
• Proteasomes are large proteolytic machines

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Regulation of Cdk activity II

• Not only cyclin concentration activates Cdk
• Complex phosphorylations and dephosphory-lations
  of Cdk are also necessary

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Different Cyclin-Cdk complexes regulate different
steps in the cycle
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Each Cyclin-Cdk complex acts on different sets of
target proteins
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Cell cycle arrest

• If one step is delayed, a control system prevents
  activation of subsequent steps
• The cell cycle can stop at specific checkpoints
• If DNA is damaged, the cycle can be stopped in G1
  before S-phase

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p53 and cancer

• P53 upregulation and phosphorylation allow DNA
  repair before replication
• Missing or mutated p53 leads to increased
  proliferation with a high rate of mutations
• In 50 of all cancers, mutations are found in the
  p53 gene

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Cells can withdraw from the Cell Cycle
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Dismantling the checkpoint system

• Some cells dont divide, e.g. neurons and muscle
  cells
• For a lifetime they persist in G0 phase
• In G0, Cdks and cyclins disappear
• Generally, mammalian cells only proliferate
  (divide), if they are stimulated by external
  factors
• Mammalian cell cycle has various checkpoints

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Extracellular cell cycle control

• Organ and body size are controlled by
• - cell growth
• - cell division
• - cell death/survival
• Animal cells need extracellular signal for all
  these processes
• Positively acting signals are
• - mitogens
• - growth factors
• - survival factors

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Mitogens

• Mitogens are secreted proteins binding to
  surface receptors
• These receptors activate signalling pathways that
  promote transition/release brakes between G1 and
  S phase
• The Retinoblastoma protein, Rb, is such a brake
• Rb is abundant in the nucleus, where it prevents
  transcription of genes necessary for
  proliferation

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Growth factors

• GF stimulate cells to grow
• Cell growth does not
  depend on the cell cycle control
  system

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Cells have very different sizes
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Survival factors

• A cell needs signals not only for proliferation
  and growth, but also for survival
• This means, that if a cell does not get survival
  factors, it will commit suicide
• Survival factors are important both during
  development and in the adult organism

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Extracellular factors inhibiting
growth

• E.g. Myostatin inhibits growth and proliferation
  of myoblasts
• Inactivation of myostatin leads to dramatic
  increase in muscle mass

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Key concepts 1

• The cell cycle consists of 4 phases G1, S, G2
  and M phase
• A regulatory system consisting of cyclins and
  Cdks coordinates activities of the cycle
• The cell cycle can be arrested at specific
  checkpoints
• Cells can be withdrawn from the cycle and go into
  G0 phase
• Extracellular factors (mitogens, growth factors
  and survival factors) regulate the cell cycle in
  animals

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Mitosis and cytokinesis, M-phase
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The M-phase

• M-phase consists of mitosis
  and cytokinesis
• Entry into M-phase is
  regulated by the M-phase
  Cdk /cyclin
• Activation leads to a series
  of visible changes, e.g.
  breakdown of nuclear
  envelope, a radical
  reorganisation of the
  cytoskeleton etc.

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Preparation for M-phase

• Chromosomes duplicated in S-phase consist of 2
  copies tightly bound together as identical sister
  chomatides
• After the start of M-phase, chromosomes condense
  to form visible thread-like structures
• The cytoskeleton takes care both of the
  mechanical division of the nucleus (mitosis) and
  of the division of the cytoplasma (cytokinesis)

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Cytoskeletal structures mediating M-phase
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The centrosome, the microtubule-organizing center
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Sister-chromatides separate in anaphase
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Cytokinesis

• Cytokinesis is the process by which cytoplasm
  is cleaved in two by a contractile ring
• The ring consists of actin and myosin

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Cell shape during the cell cycle
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Meiosis

• Genes are carried by chromsomes
• Chromosomes are portioned out into specialized
  sex cells called germ cells or gametes the egg
  and the sperm
• The gametes are haploid, i.e. they have only one
  set of chromosomes

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Sexual reproduction includes both diploid and
haploid cells

• We have in all cells except the gametes, two
  sets of chromosomes, one from each parent the
  cells are diploid
• Haploid cells are created by a process called
  meiosis. During meiosis the double chromosome set
  is partioned out, in fresh combinations, into a
  single chromosome set
• A haploid cell cannot divide
• Two different haploid gametes can fuse and make a
  new diploid cell called a zygote
• The cells from which gametes develop are called a
  germ line

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Sexual reproduction
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Why sexual reproduction?

• Good question! Chances of survival supposedly
  increase in an unpredictably changing environment
• It makes the fittest individuals attempt to
  select good genes, allowing elimination of
  bad genes more rapidly than in a sexual
  reproduction

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The meiotic process

• Two key features- Haploid cells are produced
  by one DNA replication duplicating the
  chromosomes, followed by two successive cell
  divisions. The duration is days years!
• - Meiosis involves a special process of
  chromosome pairing
• Thus, meiosis produces 4 cells that are
  genetically different and contain half as many
  chromosomes as the original parent cell (meiosis
  produces 2 identical cells)

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Chromosome pairing

• A diploid cell contains 2 very similar versions
  of each chromosome
• It has a great deal of duplicate genetic
  information
• The two versions of each chromosome are, however,
  not identical, containing different variants of
  many genes
• The alternative forms of a gene are called
  alleles
• Because the parental forms of each chromosome are
  similar not identical they are called
  homologuos chromosomes or homologs

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Division 1 in meiosis

• Homologuous paternal and maternal chromosomes
  pair up alongside each other before they line up
  in the spindle
• Pairing enables the paternal and the maternal
  homologs to be segregated to each cell

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Recombination between maternal and paternal
chromosomes

• After the duplicated chromosomes have paired,
  recombination (crossing-over) takes place i.e.
  parts of homologuous chromosomes are exchanged

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Meiosis compaired to mitosis
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Division 2 in meiosis

• 4 haploid daughter cells are produced
• The haploid cells contain extensively reassorted
  genetic information
• Due to reassortment 223 8.4 x 106 different
  gametes can be produced
• Together with recombinations due to
  crossing-over, a nearly limitless genetic
  variation can result

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Key concepts 2

• M-phase consists of mitosis and cytokinesis
• Mitosis consists of - prophase
• - prometaphase
• - metaphase
• - anaphase
• - telophase
• Chromosomes duplicated in S-phase consist of 2
  identical sister chromatides, which are
  segregated in anaphase

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Key concepts 3

• Meiosis results in 4 haploid cells that are
  genetically different and contain half as many
  chromosomes as the original parent cell
• The haploid cells are produced by one DNA
  replication followed by two cell divisions
• Recombination due to chromosomal cross-over
  results in nearly limitless genetic variation