Cancer

• proto-oncogenes:

  • code for proteins that stimulate normal cell growth and proliferation
  • eg ras gene
• proto-oncogenes --> oncogenes upon mutation

  • gain of function mutation
  • results in increase in amount of proto-oncogene product/activity of product
• tumour suppressor genes:

  • code for proteins that normally inhibit cell growth and division
  • activates cell cycle arrest, dna repair, apoptosis
  • p53 gene
• mutated tumour suppressor genes:

  • loss of function mutation, gene loses its ability to inhibit cell growth and division, allows cell to continue dividing
• gain in function mutations:

  • gene products become more hyperactive/resistant to degradation/produced excessively
  • only one allele needs to be mutated (dominant)
• loss of function mutation:

  • both alleles of the genes have to be mutated (recessive)
• dysregulation at G1 checkpoint:

  • damaged DNA from dna replication could be passed onto daughter cells
• dysregulation at G2 checkpoint:

  • if not all chromosomes replicated, chromosome number of daughter cells could be affected, damaged dna will be passed on
• dysregulation at metaphase checkpoint:

  • aneuploidy or polyploidy due to non-disjunction
• how can a gain-in-function mutation occur:

  • via change in amino acid sequence, protein becomes more active and resistant to degradation
  • base sequence of promoter of the gene increase in binding affinity by RNA polymerase
  • chromosomal translocation that leads to proto-oncogene translocated near active promoter
  • gene transposition to become under control of a more active promoter or enhancer or transposition of a more active promoter to the gene sequence
• ras gene:

  • growth factor binds to receptor, GTP binds to inactive ras protein to activate it, active ras protein then transduces signals from growth factor down the signalling pathway
• mutated ras gene:

  • leads to a constitutively active Ras protein that is always bound to GTP, even without growth factor binding to receptor
• p53 gene:

  • codes for specific transcription factor (activator)
  • p53 activator protein binds to enhancer region of DNA that codes for the synthesis of cell-cycle inhibiting proteins (for cell cycle arrest, dna repair, apoptosis)
  • loss-in-function mutation leads to these events not occurring when they should be
• genes encoding telomerase:

  • usually inactivated so that when critical length is reached, cells stop dividing
  • in cancer cells, genes are activated, lengthens shortened telomeres, precents critical length from being reached and allows for cell immortality
• genes encoding proteins involved in angiogenesis:

  • new blood vessels form within and around a growing mass of tumour cells
  • genes upregulated in cancer cells, allows tumour to grow beyond limits imposed by passive diffusion
  • tumour can obtain nutrients and oxygen and remove metabolic waste products more efficiently
• metastasis: cells from localised primary tumour leave the tumour cell mass, invade adjacent tissue and travel to other parts of the body, establishing themselves as secondary tumours
• genes encoding proteins involved in metastasis:

  • downregulation of expression of genes for cell-cell adhesion to allow cell to break away from adjacent cells
  • upregulate expression of genes for extracellular proteases to breakdown cytoskeleton and filaments holding cells together, facilitating invasion of cancer cells into the bloodstream and lymphatic system
• carcinogens:

  • nitrosamines in tobacco smoke
  • asbestos
• Qn: cancer arises via a multi-step process:

  1. a single cell accumulating mutations in genes that control regulatory checkpoints of the cell cycle
  2. types of mutations in the various genes (proto-oncogene, tumour suppressor gene), increased cell proliferation
  3. leading to uncontrolled cell division
  4. genes for angiogenesis and metastasis mutated, cancer cells invade bloodstream and then metastasise
• dysregulation of cell cycle checkpoints: cell division continues even when cell fails to meet criteria of having adequate size, replicated its DNA and having all chromosomes attached to the mitotic spindle
• G1 checkpoint checks for:

  • assessing environmental conditions like sufficient growth factors and nutrients, absence of dna damage and adequate cell size
• G2 checkpoint checks for :

  • whether DNA replication is completed, dna is undamaged, adequate cell size
• metaphase checkpoint checks for:

  • whether all centromeres are attached to kinetochore microtubules (mitotic spindle), if not anaphase will not occur
• viruses that can cause cancer:

  • Human Papilloma Viruses
  • avian sarcoma virus
  • can integrate genetic material into DNA of host cell, activate/inactivate genes or introduce oncogenes
• cancer: a group of diseases caused by uncontrolled cell division and metastasis
• the need for tight control of the mitotic cell cycle:

  • checkpoints prevent cells from dividing uncontrollably, prevents development of cancer
  • G1 checkpoint ensures cells divide only in presence of appropriate signals, checks for sufficient cell size and number of organelles
  • G2 checkpoint ensures any damaged dna is repaired
  • M checkpoint ensures microtubules are properly attached to centromeres of chromosomes before proceeding to anaphase