Cancer Flashcards
1
Q
Viral causes of Cancer
A
- Human Papilloma Virus
- Hepatitis B and C
2
Q
Cancer cells and contact inhibition
A
- 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
Q
Tumor Suppressor Gene
A
Prevent tumor development.
Come in two varieties
- Caretaker genes:
- 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
Q
Oncogenes
A
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
Q
Unilateral vs. Bilateral tumors
A
- Unilateral tumors
- Two independent mutations are required for tumor formation
- Could be heterozygous for tumor
- Accumulation of 2nd mutation leads to loss of heterozygosity
- Bilateral tumors
- Both copies are mutated
6
Q
Major inputs to p53
A
7
Q
p53 stabilization
A
8
Q
p53 mutations and cancer
A
- p53 protein has no defined tertiary structure unless it is bound to DNA (target genes)
- Oncogenic mutations destabilize p53, especially its DNAbinding domain, blocking its anti-apoptotic activity
- Drugs that stabilize p53 by preferentially binding to its folded state are in development
9
Q
Gain of Functions vs. Loss of Function
A
- Tumor Suppressor Gene
- Needs loss of function of both copies in order to promote cancer
- Recessive mutations
- Oncogene
- Needs gain of function such that protein is upregulated to promote cancer
- Dominant mutations
10
Q
Overview of Cell Cycle
A
Anything that promotes growth in the pathway is an oncogene
Anything that suppresses this growth in the pathway is a tumor suppressor gene
11
Q
mTOR pathway
A
Anything that is promoting growth is an oncogene
Anything that is suppressing growth is a tumor suppressor gene.
12
Q
c-myc
A
- Activation occurs by overproduction
- Gene amplification
- In metaphse FISH, large homogenously stained can be seen containing multiple tandem duplications
- Chromosomal translocation places c-myc gene under control of a powerful enhancer.
- Gene amplification
- Results in Burkitt’s lymphoma
- A tumor of B lymphocytes
- Transcription of antibody genes is driven by powerful B-cell-specific enhancer
- Translocations put c-myc under control of an anibody gene enhancer
- C-myc gene is transcribed at many times the normal rate
13
Q
c-abl
A
- Activation occurs by self-activation thereby being independent of normal regulatory stimuli
- Chromosomal translocation beween chromosome 9 and 22 that creates a bcr-abl fusion chromosome 22
- BCR–> 22
- ABL–>9
- Results in formation of a consitutively active c-abl protein
- bcr part of the bcr-abl protein forms oligomers
- This allows each abl kinase domain phosphorylate each other without needing the presence of a ligand.
- Gleevec binds to protein kinase domain preventing kinase from activating bcr-abl protein even though it is dimerized.
- In Normal abl protein
- The absence of a ligand results in a loop of the polypeptide chain blocking active site.
- Chromosomal translocation beween chromosome 9 and 22 that creates a bcr-abl fusion chromosome 22
14
Q
c-ras
A
- Ras is a G-protein
- GAP = NF1
- Slow intrinsic GTPase activity stimulated by GTPase activating proteins (GAP’s)
- Mutation in NF1 results in neurofibromatosis
- GEF = SOS
- GAP = NF1
- Ras controls:
- Cell growth and divison
- Cytoskeleton
- Cell Adhesion
- Membrane traffic
- Anti-apoptosis
- Upregulation would be problematic
- Oncogenic mutations in Ras
- 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
- Gln-61: needed for proper positioning of H2O to attach gamma phosphate
- Gly-12: needed for reaction of Ras-GAP
- Mutations in either of these decrease Ras-GTPase activity
- 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