Cancer Molecular Genetics 1 Flashcards

Terms Definitions
Functions of oncogenes (5)
a) Promote cell division
b) Inhibit Apoptosis
c) Promote metastasis
d) Promote angiogenesis
e) Promote immortality
Functions of tumor suppressors (5)
a) Promote Apoptosis
b) Inhibit cell division
c) Inhibit immortality
d) Inhibit metastasis
e) Inhibit angiogenesis
What can stimulate the death receptor? (3)
a) DNA damage
b) TNF alpha and Fas
c) Growth factor withdrawl
Explain how oncogenes act in a dominant fashion and tumor suppressor genes act in a recessive fashion
oncogenes when one is mutated and turned on, you will get cancer think Ras contitutively active, only need to do that once and will definitely get cancer. If a suppressor gene is mutated there is usually a second copy of the gene whose functional products will allow for adequate suppression of the oncogenic pathway. Hence it acts recessively
What are the two apoptotic pathways?
1 Death Receptor Signal Transduction Pathway
2. Mitochondrial Signal Transduction Pathway
Explain the process of getting to the caspase cascade in the death receptor pathway
Fas ligand interacts with the Fas receptor on the cytoplasmic surface of the cell, the Fas receptor then interacts with the cytoplasmic adaptor protein FADD or another with a death domain (DD) in the DISC or death inducing signal complex. In the DISC the DD interacts with procaspase 8 which autoproteolyses itself and then goes on to activate the caspase cascade
What will only induce the mitochondrial pathway (8)
hypoxia,
oxidants,
high Ca,
short telomers,
mitotic catastrophe
DNA damage (also death receptor)
Ras MAP kinase
chemotherapy drugs
Explain the process of getting to teh caspase cascade in the mitochondrial signal transduction pathway
The mitochondrial pathway is activated so Bak;Bax can form either hetero or homo dimers that aggregate to form pores in the mitochondrial membrane. Bcl2 or XL sequester Bak or Bax to prevent dimerization. Bad and Bid bind Bcl2 or XL and dissociate Bak or Bax so they can form the dimer and make the pore. The pore then allows the release of cytochrome C which aggregates with apaf1 and procaspase 9 to form the apoptososme, procaspase 9 then undergoes autoproteolysis and activates the caspase cascade
Released from the mitochondria besides cytochrome C
1. Smac/Diablo
2. AIF and EndoG
XIAP
(inhibitors of apoptosis)
an inhibitor of the caspase cascade
inhibited by Smac/Diablo
Smac/Diablo
inhibitor of XIAP which removes inhibition from the caspase cascade and is therefore pro-apoptotic
AIF and EndoG
released by the mitochondrial signal transduction pathway which promote nuclear DNA degredation
pro-apoptotic
Bid/Bad
bind Bcl2/ XL and sequester so dissociate from Bak and Bax so they can easily form the dimer to form the pore complex
pro-apoptotic
Bcl2 and BclXL
bind Bak or Bax and sequester so can't bind together to form pore complex
anti-apoptotic
MAPK activity on BcL2
phosphorylates Bcl2 which allows it to associate with a carrier protein and allows its removal of the membrane preventing it from binding Bak and Bax
pro-apoptotic
MAPK activity on Bad
phosphorylates Bad and allows it to associate with a carrier protein that removes it from the mitochondrial membrane and prevents it from interacting with Bcl2/XL and allows for inhibition by Bcl2 on the Bak Bax pore formation
anti-apoptotic
ARF and p53
when Myc and E2F are overexpressed, ARF will be activated to sequester Mdm2 so it can't bind to p53 which will then start apoptosis
example of where an ocogene overexpression will actually induce cell death
How do Damage inducing kinases affect p53
The damage inducing kinases ATM and ATR phosphorylate p53 so Mdm2 can't bind so turns on p53 and can potentially cause cell death
Metastasis
the ability of the tumor cell to migrate from the primary tumor to a different site and grow into a secondary tumor
Steps of metastasis (7)
1. benign tumor grows
2. breaks through the basal lamina
3. invades the endothelium of the a capilary
4. survive immune system in the blood cell
5. adhere to blood vessel wall
6. escape blood vessel
7. proliferate in the extracellular matrix underneath the blood vesel
type IV collagenases
are secreted by the cell upon a signal to invade the basement membrane, act on the type IV collagen in the basement membrane, is cleaved by plasmin from procollagenase to collagenase which then cleaves the basement membrane and allows for invasion
TIMP
inhibits collagenases and prevents invasion
is anti-metastatic
Tissue inhibitors of metallo proteins
Plasminogen
found in the extracellular space at all times
activated by the urokinase plasminogen activator
once cleaved becomes plasmin which cleaves procollagenase to collagenase which allows invasion, plasmin also degrades the basement memebrane without the help of collagenases
in its active form is pro metastasis
Urokinase Plasminogen Activator
cleaves plasminogen to plasmin
pro-metastasis
secreted by tumor cells
Plasminogen activator inhibitors (PAI)
inhibit plasminogen from being cleaved into active plasmin
are anti-metastatic
three step process of membrane invasion
1. tumor cells have laminin receptors on them and most cells have laminin so bind to basement membrane
2. induce the production of procollagenase type IV and UKPA secrete, moves into the extracellular matrix and activated by plasmin
3. cell then equipped with motility
angiogenesis
physiological process involving the growth of new blood vessels from pre-existing vessels.
How is angiogenesis done in tumor cells
Tumor cells are given the signal by Ras to produce VEGF and FGF which induce endothelial cells to produce Urokinase Plasminogen Activator and Procollagenases as well as PAIs and TIMP. Then proliferation and invasion into the basement membrane and invade towards the tumor
Angiostatin
when urokinase plasminogen activator cleaves plasminogen, it also creates an anti-angiogenic peptide from the N terminius which prevents angiogensis elsewhere
endostatin
when collagen 18 is cleaved by extracellular tumor protease from the c terminal end which is an antiangiogenic protein
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