Cancer causing genes

• what occurs when proto-oncogenes are mutated?

  Permanent activate of gene e.g Ras
• Are proto-oncogen mutations dominant or recessive?

  Dominant
• what does a dominant mutations mean only one copy in diploid cells needed for expression
• Are tumour suppressor gene mutations dominant or recessive?

  Recessive
• What does a mutation in a tumour suppressor gene lead to?

  inactivation of proteins
• What occurs due to a mutation in a tumour suppressor gene?

  Reduced the inhibition of cell division, thereby stimulating cell proliferation
• Retinoblastoma protein

  • tumour suppressor gene
• What are the 2 forms of retinoblastoma?

  familial (10%), sporadic (90%)
• Is retinoblastoma protein a dominant or recessive trait?

  Recessive
• Why does retinoblastoma protein express inheritance dominancy?

  As it is caused by a mixture of inheritance and somatic
• Somatic retinoblastoma cause:

  mitotic recombination

  1. normal cell - 1 good gene enough to inhibit cell divison
  2. Normal DNA duplication, results in duplication of normal ad mutant chromosomes
  3. Rare complication: simple exchange of genetic material between normal and mutant chromatids
  4. Subsequent mitotic segregtion of chromatids and cytokinesis - one cell homozygous (normal) and one cell homozygous (mutant)
• What does the retinoblastoma protein do?

  Inhibits the G1-S transition
• What occurs when there is a mutation to retinoblastoma protein?

  leads to a loss of G1 checkpoint and uncontrolled cell divison. Therefore division no longer requires stimulatio by mitogens
• Why is p53 called so?

  protein is 53 kDa
• What is the role of p53?

  Protection of the cell against damaged DNA, arrest the cell cycle giving DNA repair machinery more times to fix DNA before mitosis and passing on of the damaged DNA to daughter cells
• Why is p53 known as the guardian of the genome?

  it has a surveillance system recognises genomes damage, metabolic stress.

  p53 is constitutively expressed but constantly degraded in absence of genetic damage. In presence of genetic damage or cellular stress p53 is stabilised.

  p53 is a transcriptional regulator of multiple proteins that halt the cell cycle while the genetic damage is repaired

  If DNA damage is too severe cells can enter senescene or apoptosis
• p53 in relation to DNA damage

  1. DNA damaged in nucleus
  2. signal is passed to p53 via a cascade of protein kinases each phosphorylating and activating each other
  3. activated p53 is a transcription factor, trigger expression of proteins which inhibit cell cycle
• what is p21?

  Cdk inhibitor protein
• how are p21 and p53 expressed?

  p21 expression is up regulated by p53
• What does p21 inhibit?

  cyclin E-cdk2
• what does p21 do?

  prevents G1 exit, causing cell cycle to stop. Preventing duplication of damaged DNA and passing one of DNA to daughter cells
• DNA repair protein are transcriptionally regulated by p53

  • Their expression up regulated by p53
  • allows cells to repair DNA during cell cycle arrest
  • if DNA damage is unrepaired cells enter senescence or apoptosis. These pathways are regulated by p53
• genes involved in apoptosis

  If the DNA is damaged so badly it can not be repaired p53 activated genees which cause apoptosis (cell suicide)
• p53 alters gene expression by:

  • cdk inhibitor protein p21
  • DNA repair proteins are transcriptionally regulated by p53
  • genes involved in apoptosis
• What is apoptosis?

  A form of cell death in which a programmed sequence of events leads to the elimination of cells without releasing harmful substances into the surrounding area
• What are the stage
• what are the stages of apoptosis?

  1. normal cell 'realises' that its DNA is beyond repair and so p53 activates apoptosis
  2. cell begins to shrink and invaginations form at the cell surface
  3. organelles become enclosed in vesicles. DNA in nucleus is dissolved by enzymes, cellular material is engulfed and degradede by phagocytes
• What is necrosis?

  Necrosis is the death of cells or tissues in the body due to injury, infection, or lack of blood supply. Cells leak out
• How is apoptosis induced?

  intrinsic apoptosis

  FAS death receptor -extrinsic apoptosis
• what does p53 enhance?

  bid synthesi - damages mitochondrial membrane
• how does p53 affect extrinsic apoptosis?

  mediated in response to stimuli outside of the cell, p53 upregulates expression of death receptors on cell surface
• Bid expression

  • when DNA is damaged
  • activated Bid induces Bax to form a pore in the mitochondrial membrane
  • Release of cytochrome c activates caspases present in cytoplasm of cell leass to apoptosis
• extrinsic apoptosis = death receptor
• Death receptors

  Activated by cells expressing Fas ligand (on surface of killer lymphocytes)
• Fas ligand and receptor


  • Both are homotrimers
• Fas cytosolic tail recruitment


  Recruits the adaptor protein FADD via the death domain on each protein
• FADD

  Fas-associated death domain
• FADD recruitment of initiator procaspase

  Each FADD protein recruits an initiator procaspase (procaspase-8, procaspase-10, or both) via a death effector domain on both FADD and the procaspase, forming a death-inducing signaling complex (DISC)
• Initiator procaspase activation within DISC


  Brought into close proximity, which activates them; the activated procaspases then cleave one another to stabilize the activated protease, which is now a caspase
• Activated caspase-8 and caspase-10

  Cleave and activate executioner procaspases, producing a caspase cascade, which leads to apoptosis