BIOCELL GEN Lecture 11 cell cycle control

• Cell cycle regulation


  The frequency of cell division varies with the type of cell

  
• Cell cycle control system


  Signaling molecules in the cytoplasm drive the cell cycle
• Cancer cells escape the usual controls on the cell cycle
• Cell cycle control system


  1. Animal cells have built-in stop signals that halt the cell cycle at checkpoints until overridden by go-ahead signals

  2. The cell cycle control system is regulated at certain critical control points (checkpoints) by both internal & external system
• Major checkpoints in the cell cycle


  • G1 checkpoint
  • G2 checkpoint
  • M checkpoint
• Checkpoints


  Biochemical on/off switches that are irreversible
• G1 checkpoint


  Also known as the 'restriction point' in mammalian cells (or 'start' in yeasts)
• G1 checkpoint


  The most important checkpoint - if a cell receives a go-ahead signal, it usually completes the whole cycle and divides
• G0 phase


  1. No active cell growth or division takes place, only maintenance

  2. Cells in G0 phase can be 'recalled' to the cell cycle by external cues, such as growth factors & mitogens
• Cyclins


  Proteins whose levels cyclically change and regulate progression through checkpoints

  
• Cyclin-dependent kinases (CdKs)


  Enzymes that are activated cyclically by binding to cyclins
• Progression through cell cycle checkpoints


  1. Depends on the levels of specific proteins called cyclins

  2. Cyclins bind cyclin-dependent kinases (CdKs) and activate them

  3. 'CdK-cyclin' active complex phosphorylates downstream targets

  
• Cyclins


  • G1/S-cyclins
  • M-cyclins

  
• G1/S-cyclins

  Trigger progression through G1 checkpoint
• 1. cyclins


  Stimulate entry into mitosis at the G2 checkpoint
• Regulation of CdKs


  • By cyclin binding (complex formation)
  • By phosphorylation and dephosphorylation (both activating or inactivating)
  • By the binding of inhibitory proteins
  • By destruction of cyclins (at M checkpoint)

  
• G1 'DNA damage' Checkpoint


  1. Blocks entry into S phase

  2. DNA damage activates p53, which stimulates transcription of p21 CKI protein

  3. p21 binds to G1/S-Cdk and S-Cdk and inhibits their activity
• G2 Checkpoint


  1. Incomplete DNA replication and DNA damage blocks entry into Mitosis

  2. Signals activate protein kinases (Chk1) that phosphorylate and inactivate the phosphatase Cdc25

  3. Blocks the dephosphorylation and activation of M-Cdk, thereby blocking entry into mitosis

  
• M Checkpoint (Spindle Assembly Checkpoint – SAC)

  1. Unattached chromosomes block sister-chromatic separation

  2. Cells do not enter anaphase until all chromosomes are correctly bi-oriented

  3. Not properly attached kinetochore → "wait" signal → blocks APC/C

  4. When all chromosomes reach bi-orientation, go-ahead signal
• Cancer involves uncontrolled cell division
• These differences result from regulation at the molecular level: the cell cycle control system• Cancer cells escape the usual controls on the cell cycle• The cell cycle is driven by signaling molecules in the cytoplasm
• Accumulation of mutations in certain types of genes may lead to cancer
• Chromosomal changes often cause cancerEnvironmental causes of cancer are being studiedExposure of cells to certain chemicals and radiation increases mutations and thus the chance of cancer
• P53 is called ‘the bodyguard of the genome’
• P53 proteins triggers cell suicide (apoptosis) in cells with damaged DNA = halt of damaged cell growth and division
• p53 mutations:→ frequent in tobacco-related cancers→ higher incidence of mutations in cancers from smokers than from non-smokers
• every cell division carries a small but non-negligible risk of introducingmutations in the daughter cell→some of those mutations could lead to cancer
• large-bodied, long-lived animals→would have a greater risk of cancer than small, short-lived ones
• Peto’s paradox


  Lack of correlation’ between body size & cancer risk.

  This suggests that mechanisms that can suppress cancer 1,000 times more effectively than is done in human cells
• elephants have 20 extra copies of p53 tumor suppressor gene, humans have 1