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BMS 2 Week 3 > Cancer > Flashcards

Flashcards in Cancer Deck (14):
1

Viral causes of Cancer 

  1. Human Papilloma Virus
  2. Hepatitis B and C

2

Cancer cells and contact inhibition

  • Cancer cells are immune to contact inhibition
    • Normally, neighboring cells send signals to cell to stop proliferating and migrating irregularly
  • Cancer cells lose cadherins which promote detachment from other cells and invasion into neighboring tissue
  • Cancer cells do not sample environment or ECM before undergoing cell division
  • Cancer cells metalloproteases that degrade ECM and facilitate tissue invasion. 

3

Tumor Suppressor Gene 

Prevent tumor development. 

Come in two varieties

  1. Caretaker genes: 
    1. Products prevents damage or repairs damage to

      DNA.

    2. Loss of protein function is not oncogenic itself but

      promotes further genetic change/increases chance.

    3. I.e. MLH, XRCC1, BRCA1/2

  2. Gatekeeper genes:

    1. Products restrain cell division or induce apoptosis, if cells initiate division when they should not.

    2. Loss of protein function allows uncontrolled proliferation directly.

    3. I.e. Rb --> controls G1/S transition

    4. P53 halts cell division or initiates apoptosis in response to DNA damage. 

4

Oncogenes 

Products promote cell growth and division

  • Mutations in these genes do not inactivate their proteins but cause loss of normal control so that continuous activity drives cell divsion 

5

Unilateral vs. Bilateral tumors 

  1. Unilateral tumors
    1. Two independent mutations are required for tumor formation 
    2. Could be heterozygous for tumor
    3. Accumulation of 2nd mutation leads to loss of heterozygosity
  2. Bilateral tumors
    1. Both copies are mutated 

6

Major inputs to p53

7

p53 stabilization 

8

p53 mutations and cancer

  1. p53 protein has no defined tertiary structure unless it is bound to DNA (target genes)

  2. Oncogenic mutations destabilize p53, especially its DNAbinding domain, blocking its anti-apoptotic activity

  3. Drugs that stabilize p53 by preferentially binding to its folded state are in development

9

Gain of Functions vs. Loss of Function

  1. Tumor Suppressor Gene
    1. Needs loss of function of both copies in order to promote cancer
    2. Recessive mutations 
  2. Oncogene
    1. Needs gain of function such that protein is upregulated to promote cancer
    2. Dominant mutations

10

Overview of Cell Cycle 

Anything that promotes growth in the pathway is an oncogene

Anything that suppresses this growth in the pathway is a tumor suppressor gene

11

mTOR pathway 

Anything that is promoting growth is an oncogene

Anything that is suppressing growth is a tumor suppressor gene. 

12

c-myc

  1. Activation occurs by overproduction
    1. Gene amplification
      1. In metaphse FISH, large homogenously stained can be seen containing multiple tandem duplications
    2. Chromosomal translocation  places c-myc gene under control of a powerful enhancer. 
  2. Results in Burkitt's lymphoma
    1. A tumor of B lymphocytes 
    2. Transcription of antibody genes is driven by powerful B-cell-specific enhancer
    3. Translocations put c-myc under control of an anibody gene enhancer
    4. C-myc gene is transcribed at many times the normal rate 

13

c-abl

  1. Activation occurs by self-activation thereby being independent of normal regulatory stimuli 
    1. Chromosomal translocation beween chromosome 9 and 22 that creates a bcr-abl fusion chromosome 22
      1. BCR--> 22
      2. ABL-->9 
    2. Results in formation of a consitutively active c-abl protein
      1. bcr part of the bcr-abl protein forms oligomers 
      2. This allows each abl kinase domain phosphorylate each other without needing the presence of a ligand. 
      3. Gleevec binds to protein kinase domain preventing kinase from activating bcr-abl protein even though it is dimerized. 
    3. In Normal abl protein
      1. The absence of a ligand results in a loop of the polypeptide chain blocking active site. 

14

c-ras

  1. Ras is a G-protein
    1. GAP = NF1
      1. Slow intrinsic GTPase activity stimulated by GTPase activating proteins (GAP's)
      2. Mutation in NF1 results in neurofibromatosis
    2. GEF = SOS 
  2. Ras controls:
    1. Cell growth and divison
    2. Cytoskeleton
    3. Cell Adhesion
    4. Membrane traffic 
    5. Anti-apoptosis 
    6. Upregulation would be problematic
  3. Oncogenic mutations in Ras
    1. Amino acid substitutions at just two position that reduce intrinsic GTPase activity of Ras thereby allowing it to spend more time in teh active state
      1. Gln-61: needed for proper positioning of H2O to attach gamma phosphate
      2. Gly-12: needed for reaction of Ras-GAP 
        1. Mutations in either of these decrease Ras-GTPase activity