Cell cycle

• Why is correct regulation of cell division important?

  development (correct organ and body part need to be correct)

  injury (cells need to divide following an injury but stop when damage is repaired)

  adaptive response (cells in bone marrow in response to low O2), (lymphocytes division triggered in response to antigen - needs to be controlled)
• Consequences of deregulated cell division: cancer
• Two main ways in which cell division is regulated

  external signals

  internal signal
• External signal: diffusable chemical signals produced by other cells which 'tell the cell in question how to behave ' e.g growth factors (mitogens)
• Internal signals: chemical signals produced internally by the cell itself in order to regulate its own division - present in tthe cytoplasm of cell e.g cyclin dependent kinases
• What signal regulates the cell cycle progression?

  External signal
• What are growth factors also known as?

  mitogens
• What occurs in the absence of mitogens?

  s phase cyclins are not made
• What are s phase cyclin?

  Cyclins which drive the cell into s phase
• What occurs without sustained mitogen stimulation?

  can't progress through the G1 checkpoint
• What occurs when cells can't pass through G1 checkpoint?

  cells enter G0 also known as quiet phase or quiescence
• mitogens activates which type of receptor?

  transudction pathway, this leads to increased cyclin expression
• Platelet-derived growth factor:

  • external growth factor
  • released in response to injury
  • PDGF binds to receptors on surface of skin cells and causes them to start dividing
• How do we know that cells have internal chemical signals which can regulate cell division?

  • cell fusion experiment concludes there is a mitosis promoting factor in M phase cells
  • but cells at any stage of the cycle can be stimulated by phase cells to enter mitosis, the response is not unique to G2 cell
  • there is a s-phase promoting factor in S-phase cells
  • although there is an S-phase promoting factor in s-phase cells, only G1 cells repsond to this factor (not G2)
• Internal signals

  M + G2

  M+G1 or S

  G1+ S

  G1 +G2
• Why does the cell need internal signals to control division?

  To prevent cancer

  Checkpoints enable cells to stop dividing if correct signals are not present

  Checkpoints allow to review current circumstances and prevent untimely exit from each cell cycle phase

  inappropraite continuation leads to genetic instability (leads to cancer)
• 3 major checkpoints

  1. G1
  2. G2
  3. metaphase checkpoint or spindle assembly checkpoint
• G1 checkpoint

  Commits cell to DNA replication and cell division

  checks if:

  • cell is a suitable size
  • received appropriate external signals
• G2 checkpoint:

  Cell makes decision whether or not to enter mitosis

  checks if:

  • cell is suitable size
  • DNA is replicated
  • environment is favourable
• M checkpoint

  occurs in metaphase

  checks if:

  • all the chromosomes are attached to spindles
• Which internal molecular signals regulate G1 and G2 checkpoints?

  Cyclin-dependent kinases and cyclins
• What did Tim hunt discover?

  Cyclin proteins

  noted that sea urchins early embryos divided synchronously. Whole population of cells at same stage of cell cycle as opposed to a mixed population at different stages. proteins levels of which increased and decreased (cycled) between interphase and mitotic phase (cyclins)
• Two stages of cyclins in cell cycle:

  synthesis in interphase, degradation in mitosis
• Action of Cdk and cyclin protein: combination of the two proteins known as a promoting factor, which controls progression of the cell into the next phase of the cell cycle
• Basic mechanism of action of Cdk and cyclin proteins: Cdk binds to the cyclin and phosphorylates the target protein
• Which cyclin and Cdk join to regulate the G1 checkpoint (S phase promoting factor)?

  cyclin E and Cdk2

  • phosphorylates proteins required fro s-phase entry
• Which cyclin and Cdk are used regulates the G2 checkpoint (m phase promoting factor or maturation promoting factor)?


  cyclin B and cdk 1

  drives cell into m phase
• do cdk levels change through the cell cycle?

  No they remain constant, activity is enhanced by changes in cyclin level.
• MPF and regulation of the cell cycle

  • Peaks of MPF activity correlate with peaks of cyclin levels. Cyclin B particularly during G2, decreases during M, maximum in early M
• What happens to cyclin B after mitosis?

  degradation increases (ubiquitination and proteosomal) - MPF activity decreases again
• Activation of MPF in G2 phase

  1. cyclin B accumulates
  2. cyclin B and Cdk1 bind to form MPF
  3. MPF triggers mitosis
  4. MPF activates cyclin-degrading enzyme
  5. enzyme degrades cyclin
  6. loss of cyclin inactivates enzyme
  7. Cdk1 is recycled
• cyclin binds to CDK and forms the active MPF complex which acts directly by causing the nuclear envelope to fragment, and indirectly by stimulating other kinases

  cycli even initiates the process which results in its own destruction - thus switching itself off
• Metaphase checkpoint:

  • checkpoint that divides the metaphase and anaphase of mitosis
  • Ensures that all chromosomes are attached to mitotic spindle before anaphase commences
  • Internak regulator is not CDK but a complex of proteins called the anaphase promoting complex
• Metaphase checkpoint

  unattached kinetochores - inhibitory pathway active

  Chromosomes is bound in cohesin known as the inactive anaphase promoting complex

  Wait signal stops when all kinetochores attached. Cohesin ubiquitination and break down. Anaphase inititated, active anaphase promoting complex
• Correct regulation of cell division is important