Regulation of Cell Division

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					Cell division, cell growth, cell Cycle
    • Interphase and meiosis I

 INTERPHASE                                  MEIOSIS I: Separates homologous chromosomes

                                      PROPHASE I                 METAPHASE I                   ANAPHASE I

                                        2. cross over

    Centrosomes                                                Centromere                        Sister chromatids
(with centriole pairs)                                      (with kinetochore)                   remain attached
                                             Chiasmata                           Metaphase
                         chromatids                                                plate

                                                         Microtubule              Homologous
                                    Tetrad               attached to             chromosomes
                                                         kinetochore                separate
Chromosomes duplicate                                               Tertads line up             Pairs of homologous
                            Homologous chromosomes                                             chromosomes split up
                         (red and blue) pair and exchange
Figure 13.8
                         segments; 2n = 6 in this example

                            1. Synapsis (聯會)
                         (synaptonemal complex)
      • Telophase I, cytokinesis, and meiosis II

                                                        MEIOSIS II: Separates sister chromatids
    TELOPHASE I AND               PROPHASE II              METAPHASE II                   ANAPHASE II              TELOPHASE II AND
      CYTOKINESIS                                                                                                    CYTOKINESIS

                                      Cleavage                                                                        Haploid daughter cells
                                      furrow                                                 Sister chromatids        forming

              Two haploid cells
              form; chromosomes                  During another round of cell division, the sister chromatids finally separate;
Figure 13.8   are still double                   four haploid daughter cells result, containing single chromosomes
         • A comparison of mitosis and meiosis
                          MITOSIS                                                               MEIOSIS
                                                          Parent cell                    Chiasma (site of
                                                                                                                           MEIOSIS I
                                               (before chromosome replication)           crossing over)

  Prophase                                                                                                                 Prophase I
                                           Chromosome                  Chromosome
                                            replication                 replication                             Tetrad formed by
Duplicated chromosome                                       2n = 6                                              synapsis of homologous
(two sister chromatids)                                                                                         chromosomes

                                              Chromosomes            Tetrads
                                              positioned at the      positioned at the                                 Metaphase I
                                              metaphase plate        metaphase plate

  Anaphase                                   Sister chromatids    Homologues
  Telophase                                  separate during      separate                                             Anaphase I
                                             anaphase             during                                               Telophase I
                                                                  anaphase I;
                                                                  sister                                               Haploid
                                                                  chromatids                 Daughter                   n=3
                                                                  remain together             cells of
                                                                                             meiosis I
                     2n                             2n
                          Daughter cells                                                                                   MEIOSIS II
                            of mitosis
                                                                                    n           n           n          n
                                                                                         Daughter cells of meiosis II
                                                                  Sister chromatids separate during anaphase II
Cell cycle:
 --- the life of a cell from the time it is first formed from a
     dividing parent cell until its own division into two cells.
 Smallest unit of life
     all living things must reproduce
 Cells replicate for growth, replacement, and repair

Cell division functions in reproduction, growth, and renewal.

                                       200 µm                      20 µm
              Cell Cycle
         The Cell’s Time Clock
•   Cell division requires Mitosis &
    Cytokinesis                           Cytokinesis
•   Phases of a dividing
    cell’s life
     – interphase
            • cell grows
            • replicates chromosomes
            • produces new organelles &
     – mitotic phase
            • cell separates & divides
                 – mitosis
            • cell divides cytoplasm &
                 – cytokinesis
       Cell cycle
    • Cell has a “life cycle”
              cell is formed from
              a mitotic division

cell grows & matures                 cell grows & matures
to divide again                       to never divide again

     G1, S, G2, M            liver cells           G0

   epithelial cells,                       brain nerve cells
   blood cells,
   stem cells
• Cell performs normal                   Interphase
• Three subphases:
   – G1: cell duplicates most
   – S: quantity of DNA in the cell is
     doubled as chromosomes are
     replicated. Each chromosome
     has a pair of sister chromatids
     connected by a centromere that
     contains a kinetochore
   – G2: chemical components
• Nucleolus present
• Nuclear division       • Mitotic events can be
  without a reduction in   categorized into
                           discrete stages based
  chromosome number        on what is happening to
• Each new cell            structure of the cell
  (daughter cell) will   • Stage include:
  have the same             – Prophase
                               • Prometaphase
  quantity of DNA as the
                            – Metaphase
  parental cell             – Anaphase
• Why is this important?    – Telophase
(Including Prometaphase)

• Pro
• Three things visibly
   – Chromosomes condense
   – Centrosomes migrate to
     the poles while
     producing spindle fibers
   – Nuclear membrane
                          Metaphase Plate

• Meta
• Chromosomes are
  moved by growing
  spindle fibers to the
  equator of the cell
  (metaphase plate)
• Centrosomes are at
  the poles, nuclear
  membrane is gone
• Ana
• Centromere splits into
• Spindle fibers shorten
  from kinetochore end
  separating sister
• Activated kinetochores
  “pull” chromatids along
  the spindle fibers and
  toward the poles
• Telo
• Nuclear membrane
  reforms around
  each region of
• Nucleolus reforms
• Cytokinesis
  (division of the
  cytoplasm) may
Cytokinesis May Vary Between Major
         Taxonomic Groups
                               Cytokinesis divides the cytoplasm

                 * Cleavage furrow                           * No cleavage furrow

            Cleavage furrow                  100 µm
Actin                                                           Vesicles     Wall of                    1 µm
  +                                                             forming      patent cell   Cell plate
                                                                                                        New cell wall
                                                                cell plate

         Contractile ring of
                                           Daughter cells
                                                                                                    Daughter cells
                 (a) Cleavage of an animal cell (SEM)       (b) Cell plate formation in a plant cell (SEM)
Regulation of Cell Division

          Coordination of cell division

• A multicellular organism needs to coordinate
  cell division across different tissues & organs
  – critical for normal growth,
    development & maintenance
     • coordinate timing of
       cell division
     • coordinate rates of
       cell division
     • not all cells can have the
       same cell cycle
        Activation of cell division

• How do cells know when to divide?
  – cell communication signals
     • chemical signals in cytoplasm give cue
     • signals usually mean proteins
         – activators
         – inhibitors

   experimental evidence: Can you explain this?
              Frequency of cell division

• Frequency of cell division varies
  by cell type
   – embryo
       • cell cycle < 20 minute
   – skin cells
       • divide frequently throughout life
       • 12-24 hours cycle                                 metaphase anaphase
   – liver cells                                        prophase         telophase
       • retain ability to divide, but keep it in       G2
       • divide once every year or two                    interphase (G1, S, G2 phases)
                                                          mitosis (M)
   – mature nerve cells & muscle cells                    cytokinesis (C)                 G1
       • do not divide at all after maturity
       • permanently in G0
                                                        There’s no
         Overview of Cell Cycle Control                 turning back,

         • Two irreversible points in cell cycle
              – replication of genetic material
              – separation of sister chromatids
         • Checkpoints
              – process is assessed & possibly halted
                                 sister chromatids

centromere                                                  
        single-stranded   double-stranded
        chromosomes       chromosomes
            Cell Cycle Regulation

• Cell cycle events are triggered by the cell-
  cycle control system; a set of molecules found
  in the cytoplasm affected by internal and
  external controls
• Checkpoints in G1, G2, and M phases of the
• G1 checkpoint is most critical. May throw cells
  out of cyclic phase into G0, never to divide
  Other Internal and External Factors
• Internal
  – M checkpoint does not proceed until signal is received that
    all kinetochores are attached to spindle microtubules
• External
  – Growth factors: cycle will not proceed if requirements are
    not met
  – Social signals
      • Density-dependent inhibition: under crowded conditions chemical
        requirements are insufficient to allow cell growth
      • Anchorage dependence: some cells must be attached to a substrate
        in order to replicate
  – DNA damage inhibits growth
External signals: ex. Growth factors
~ Cells fail to divide if an essential nutrient is left out of the
  culture medium.
~ GFs trigger a signal transduction pathway that allows the
 cells to pass the G1 checkpoint and divide.



                                                                        Signal transduction

                                                                            Cell division
      External signals

• Growth factors
   – coordination between cells
   – protein signals released by body cells
     that stimulate other cells to divide
      • density-dependent inhibition
         – crowded cells stop dividing
         – each cell binds a bit of growth factor
            » not enough activator left to trigger
              division in any one cell
      • anchorage dependence
         – to divide cells must be attached to a
            » “touch sensor” receptors
External signals: physical factor

Density-dependent inhibition of cell division
~ Crowded cells stop
                                          Cells anchor to dish surface and
  dividing                                divide (anchorage dependence).

                                          When cells have formed a complete
             single layer                 single layer, they stop dividing
                                          (density-dependent inhibition).

                                          If some cells are scraped away,
                                          the remaining cells divide to fill the
                                          gap and then stop (density-
                                          dependent inhibition).

                                                            25 µm
 • Most animal cells exhibit anchorage dependence
      – In which they must be attached to a substratum to divide

  Anchorage dependence

* Cancer cells:                 Normal cell ~ single layer
 ~ Exhibit neither density-                Cancer cells do not exhibit anchorage
                                           dependence or density-dependent
     dependent inhibition nor              inhibition.
     anchorage dependence

                                                                             25 µm

                                                               25 µm
                  Growth factor signals

growth factor

                                                   nuclear pore

                                     nuclear membrane
                                 P                                   cell division
  cell surface                                                            Cdk
        protein kinase                      P                  E2F
        cascade                                                       chromosome
                                                        Rb F          P
                                                                     Rb    nucleus
        Internal signal of a Growth Factor
  • Platelet Derived Growth Factor (PDGF)
        – made by platelets in blood clots
        – binding of PDGF to cell receptors stimulates cell
          division in fibroblast (connective tissue)
           • heal wounds

Don’t forget
to mention
The sequential events of the cell cycle are directed by a
distinct cell cycle control system, a cyclically operating set of
molecules in the cell that both triggers and coordinates key
events in the cell cycle.

                    G1 checkpoint                 ~ similar to a clock

                                                   The cell cycle is regulated
                          Control                  at certain checkpoints by
                          system    S
                                                   both internal and external

M checkpoint
                    G2 checkpoint
      Checkpoint control system
• Checkpoints
  – cell cycle controlled by STOP & GO chemical
    signals at critical points
  – signals indicate if key cellular
    processes have been
    completed correctly
      Checkpoint control system

• 3 major checkpoints:
  – G1/S
    • can DNA synthesis begin?
  – G2/M
    • has DNA synthesis been completed
    • commitment to mitosis
  – spindle checkpoint
    • are all chromosomes attached to
    • can sister chromatids separate
                                                 Spindle checkpoint
G2 / M checkpoint
                                                             Chromosomes attached at
   • Replication completed                                   metaphase plate
   • DNA integrity
                       Active                                Active
            Inactive            Cdk / G2        M     APC              cytokinesis
                                cyclin (MPF)                   C
                        G2                     mitosis


                                S                   Cdk / G1
MPF = Mitosis                                              Active
Promoting Factor                G1 / S checkpoint             • Growth factors
APC = Anaphase                                                • Nutritional state of cell
Promoting Complex                                             • Size of cell
        G1/S checkpoint

• G1/S checkpoint is most critical
  – primary decision point
     • “restriction point”
  – if cell receives “GO” signal, it divides
     • internal signals: cell growth (size), cell nutrition
     • external signals: “growth factors”
  – if cell does not receive
    signal, it exits cycle &
    switches to G0 phase
     • non-dividing, working state
             G0 phase

• G0 phase
  – non-dividing, differentiated state
  – most human cells in G0 phase
                       § liver cells
                           § in G0, but can be “called
                             back” to cell cycle by
                             external cues
                       § nerve & muscle cells
                           § highly specialized;
                             arrested in G0 & can never
                          Cell Cycle Checkpoints
•   If cell size inadequate

     – G1 or G2 arrest
•   If nutrient supply inadequate

     – G1 arrest
•   If an essential external stimulus is lacking

     – G1 arrest (at R)
•   If the DNA is not replicated

     – S arrest
•   If DNA damage is detected

     – G1 or G2 arrest
•   If the spindle formation is improper,
    chromosome misalignment                        R
     – M-phase arrest
         “Go-ahead” signals
• Protein signals that promote cell growth &
  – internal signals
     • “promoting factors”
  – external signals
     • “growth factors”
• Primary mechanism of control
  – phosphorylation
     • kinase enzymes
     • either activates or inactivates cell signals
                                        inactivated Cdk
     Cell cycle signals

• Cell cycle controls
   – cyclins
     • regulatory proteins
     • levels cycle in the cell
  – Cdk’s
     • cyclin-dependent kinases                           activated Cdk
     • phosphorylates cellular
        – activates or inactivates
  – Cdk-cyclin complex
     • triggers passage through
       different stages of cell cycle
               Types of Cyclins and Cdks
• There are many types of cyclins, but the 4 main ones are:

   –   Cyclin D (G1 cyclin)
   –   Cyclin E (S-phase cyclin)
   –   Cyclin A (S-phase and mitotic cyclin)
   –   Cyclin B (mitotic cyclin)

• These are the 3 main cdks
   – Cdk4 (G1 Cdk)
   – Cdk2 (S-phase Cdk)
   – Cdk1 (mitotic Cdk)

• The complex of Cdk1 and cyclin B is called mitosis promoting
  factor (MPF) a.k.a maturation promoting factor
                       Rise and fall of cyclins
Cyclin Concentration

                                      Cdks and cyclins
Cyclin-dependent kinases (Cdks) are enzymes that are present in the cell cytoplasm at all times.

However, they are inactive unless they are bound by a specific partner-protein called a cyclin to form a
Cdk-cyclin complex

The amount of cyclins in the cell changes – because they get degraded

A Cdk-cyclin complex will push the cell cycle forward.
Figure 19-35 Phosphorylation and Dephosphorylation in
          the Activation of a Cdk-Cyclin Complex
       MPF: M-phase Promoting Factor

• MPF is composed of two key subunits: Cdc2
  and Cyclin B.
  – Cdc2 is the protein that encoded by genes
    which are required for passage through START
    as well as for entry into mitosis.
  – Cyclin B is a regulatory subunit required for
    catalytic activity of the Cdc2 protein kinase.
                   What does MPF do?
The complex of Cdk1 and cyclin B is called mitosis promoting factor (MPF)
 MPF activity is dependent upon Cyclin B

• The cyclins were identified as proteins
  that accumulate throughout interphase
  and are rapidly degraded toward the end
  of mitosis.
• It is suggested that they might function to
  induce mitosis, with their periodic
  accumulation and destruction controlling
  entry and exit from M phase.
  MPF activity is dependent upon Cyclin B

• Accumulation and degradation of cyclins
Figure 19-34 Fluctuating Levels of Mitotic Cyclin and MPF
                    During the Cell Cycle
                 MPF regulation
• Cdc2 forms complexes with cyclin B during S and G2.
• Cdc2 is then phosphorylated on threonine-161, which
  is required for Cdc2 activity, as well as on tyrosine-15
  (and threonine-14 in vertebrate cells), which inhibits
  Cdc2 activity. Dephosphorylation of Thr14 and Tyr15
  activates MPF at the G2 to M transition.
• MPF activity is then terminated toward the end of
  mitosis by proteolytic degradation of cyclin B.
                      MPF regulation
• Demonstration of regulation of MPF
Figure 19-40 A General Model for Cell Cycle Regulation
                                         1970s-’80s | 2001
                          Cyclins & Cdks
• Interaction of Cdk’s & different cyclins triggers the stages of
  the cell cycle

     Leland H. Hartwell       Tim Hunt   Sir Paul Nurse
     checkpoints              Cdks       cyclins
• external signals is
  inhibition, in which
  crowded cells stop
  dividing but lost of
  contact inhibition
  and outgrowth in
  cancer cells
• Mass of abnormal cells
  – Benign tumor
    • abnormal cells remain at original site as a lump
       – p53 has halted cell divisions
    • most do not cause serious problems &
      can be removed by surgery
  – Malignant tumors
    • cells leave original site
       – lose attachment to nearby cells
       – carried by blood & lymph system to other tissues
       – start more tumors = metastasis
    • impair functions of organs throughout body

     •   Benign - A spontaneous growth of
         tissue which forms an abnormal
         mass is called a tumor. A tumor
         that is noninvasive and
         noncancerous is referred to as a
         benign tumor.

     •   Malignant - A tumor that invades
         neighboring cells and is cancerous
         is referred to as a malignant tumor.

     •   Matastasis – Cancer that has
         spread to other tissues.
          Development of Cancer

• Cancer develops only after a cell experiences ~6 key
  mutations (“hits”)
   – unlimited growth
      • turn on growth promoter genes
   – ignore checkpoints
      • turn off tumor suppressor genes
   – escape apoptosis
      • turn off suicide genes
                                                  It’s like an
   – immortality = unlimited divisions            out of control
      • turn on chromosome maintenance genes      car!
   – promotes blood vessel growth
      • turn on blood vessel growth genes
   – overcome anchor & density dependence
      • turn off touch censor gene
         Cancer & Cell Growth
     • Cancer is essentially a failure
       of cell division control
             – unrestrained, uncontrolled cell growth
     • What control is lost?
             – checkpoint stops
             – gene p53 plays a key role in G1 checkpoint
                • p53 protein halts cell division if it detects damaged DNA
p53 is the
Cell Cycle         –   stimulates repair enzymes to fix DNA
Enforcer           –   forces cell into G0 resting stage
                   –   keeps cell in G1 arrest
                   –   causes apoptosis of damaged cell
                • ALL cancers have to shut down p53 activity

                           p53 discovered at Stony Brook by Dr. Arnold Levine
               p53 — master regulator gene
                                                                                        p53 allows cells
                                                                                        with repaired
                                                                                        DNA to divide.
                   protein                   DNA repair enzyme

Step 1                                Step 2                          Step 3
DNA damage is caused                  Cell division stops, and        p53 triggers the destruction
by heat, radiation, or                p53 triggers enzymes to         of cells damaged beyond repair.
chemicals.                            repair damaged region.


                   p53 protein

 Step 1                      Step 2                                                                  cell
 DNA damage is               The p53 protein fails to stop       Step 3
 caused by heat,             cell division and repair DNA.       Damaged cells continue to divide.
 radiation, or               Cell divides without repair to      If other damage accumulates, the
 chemicals.                  damaged DNA.                        cell can turn cancerous.
      Growth Factors and Cancer

• Growth factors influence cell cycle
  – proto-oncogenes
     • normal genes that become oncogenes (cancer-
       causing) when mutated
     • stimulates cell growth
     • if switched on can cause cancer
     • example: RAS (activates cyclins)
  – tumor-suppressor genes
     • inhibits cell division
     • if switched off can cause cancer
     • example: p53
        What causes these “hits”?

• Mutations in cells can be triggered by
  u UV radiation           u cigarette smoke
  u chemical exposure      u pollution
  u radiation exposure     u age
  u heat                   u genetics
   How we naturally fight cancer cells
• Tumor suppressor genes like p53
  – Can arrest the cell cycle
  – Can launch the apoptotic pathway, causing the
    rogue cells to lyse
  A mutation in the p53 gene can lead to cancer

• Immune cells (WBCs) such as NK cells can
  attack and lyse tumor cells
  – Some immune cells can signal the rogue cells to
    launch the apoptotic pathways
    Traditional treatments for cancers
•   Treatments target rapidly dividing cells
     – high-energy radiation
         • kills rapidly dividing cells
     – chemotherapy
         • stop DNA replication
         • stop mitosis & cytokinesis
         • stop blood vessel growth
              New “miracle drugs”

• Drugs targeting proteins (enzymes) found
  only in tumor cells
  – Gleevec
     • treatment for adult leukemia (CML)
       & stomach cancer (GIST)
     • 1st successful targeted drug
Any Questions??
     Signal Transduction Pathways
• What are they?
   – Signal transduction refers to any process by which a cell
     converts one kind of signal or stimulus into another.
   – A large number of proteins, enzymes and other molecules
     participate in a "signal cascade“

• What is the end result?
   – Either the activation or inhibition of a certain enzyme in
     the cytoplasm
   – Either the expression or suppression of a particular gene
Just a few examples of Signal Transduction

•   Cell Division signals
•   Apoptotic signals
•   Insulin pathways
        Insulin Signaling Pathway

The binding of insulin to its receptor on a cell starts a cascade of
cellular events which finally leads to the uptake of glucose and the
lowering of blood glucose levels.
         “Go-ahead” signals
• Protein signals that promote cell growth &
  – internal signals
     • “promoting factors”
  – external signals
     • “growth factors”
• Primary mechanism of control
  – phosphorylation
     • kinase enzymes
     • either activates or inactivates cell signals

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