Cancer

• Molecular Carcinogenesis


  The study of the molecular basis of cancer development

  
• Cyclins


  Proteins that control the cell cycle by binding to and activating cyclin-dependent kinases (CDKs)

  
• CDKs (Cyclin-dependent kinases)


  Family of kinases that regulate the transition from G1 to S and from G2 to M phases of the cell cycle

  
• CDKIs (Cyclin-dependent kinase inhibitors)


  Proteins that inhibit the activity of CDKs, thereby regulating the cell cycle

  
• Role of cyclins, CDKs, CDKIs in regulating the cell cycle

  1. CDKs interact with cyclins and control the cell cycle by phosphorylating other proteins

  2. Cyclin specifies the protein targets for CDK

  3. Phosphorylation by CDKs can activate or inactive a protein

  
• Cancer cells have a higher rate of mutation than normal cells

  
• Enzymatic systems that repair DNA damage or mistakes during replication are often defective in cancer cells

  
• Tumor-suppressor genes


  Genes that normally function to slow down or stop cell division, but when mutated can lead to cancer

  
• Proto-oncogenes


  Normal genes that can become cancer-causing (oncogenes) when mutated

  
• Four components of a signaling system

  • Growth factors
  • Receptors
  • Signal transducers
  • Transcription factors

  
• Growth factors


  Extracellular hormones or cell-bound signals that stimulate or inhibit cell proliferation
• Receptors


  Comprised of a signal-binding site outside the cell, a transmembrane segment, and an intracellular domain
• Signal transducers


  Located in the cytoplasm and relay the signal inside the cell
• Transcription factors


  Activate expression of specific genes to either promote or inhibit cell proliferation
• Tumor suppressors


  • Rb (retinoblastoma protein)
  • p53

  
• Tumor suppressors


  • May function in cell proliferation machinery (to slow it down), components of cell-cycle checkpoints, DNA damage repair, or to promote cell death
  • Act recessively to promote cancer - loss of function in both alleles results in increased proliferation

  
• Retinoblastoma tumor-suppressor gene


  This person has a dominant predisposition to cancer - every cell has one mutant allele. The cancer is a recessive trait - one cell gained a second mutant allele.

  
• Checkpoints


  • Not essential for cell division, but help prevent transmission of genomic instability (point mutations, translocations, gene amplification)

  
• Oncogenes


  Act in a dominant fashion to promote cancer - gain-of-function mutation results in increased proliferation

  
• Identifying oncogenes


  1. Tumor-causing viruses (retroviruses, DNA viruses)

  2. Transforming normal cells with tumor DNA

  
• RAS oncogene


  Mutant form of the RAS proto-oncogene that is constitutively activated
• Her overexpression is due to gene amplification
• Chemotherapy


  Drugs that may kill cancer cells that are unreachable or missed by surgery, directed against pathways needed for cell proliferation, but have side effects as they also kill normal proliferating cells
• New drugs targeting oncogene products

  • Gleevec (binds to and inactivates the Bcr/c-Abl enzyme)
  • Herceptin (antibody that binds to and prevents activation of the Her2 receptor)