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dr.fizzle
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What are the 4 types of cyclin CdK's?
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What activates a CdK?
- Binding of:
- Cyclin
- Phosphorylation
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Which two CdK's are triggered by mitogen?
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What gets phosphorylated and releases E2F?
Rb
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What two genes activated by myc lead to Rb phosphorylation?
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What ubiquitin ligase degrades p53?
Mdm2
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What does protein kinase ATM do?
Phosphorylates p53 so Mdm2 can no longer bind to it and degrade it
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How can p53 halt the cell cycle?
Once p53 is active it binds to p21--p21 levels increase and the inhibitor protein binds (hugs) the G1/S-CdK and the G1-CdK keeping it in an inactive state
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Is CAK or Wee1 the activating phosphatase when activating M-CdK?
CAK
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How does CDC25 remove the inhibiting phosphate?
CDC25 is phosphorylated via S-CdK and removes it
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How many checkpoints are in the cell cycle?
3 total
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When does the G2 checkoint occur?
Right before M phase
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How does M-CdK activate the APC?
It phosphorylates the APC allowing CdC20 to bind to it
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What does APC do when it is active?
It ubiquinates the securin--the securin degredation activates seperase
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What does seperase do?
It cleaves the cohesions and allows the sister chromatids to be pulled apart
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What 7 genes could you knock out that would lead to cell proliferation?
p1, p21, p27, p53, securin, ATM, Rb
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What is necrosis?
Accidental cell death
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What are the characteristics of apoptosis?
- Cell shrinks & membrane blebbing occurs
- The nucleus condenses
- DNA fragments into mono & oglionucleosomes
- Apoptotic bodies are ingested by macrophages
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What signals phagocytosis of the apoptoic bodies?
phosphatidylserine on the outer layer of the plasma membrane
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Name 2 examples of apoptosis in health?
- Shedding of the endometrium during mensturation
- Neutrophils during an acute inflammatory response
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Name two post- mitotic cells that undergo apoptosis due to aging?
- cardiac myocytes
- skeletal myocytes
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Is procaspase active or inactive?
Inactive
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Mitochondrial medicated signaling is induced if there is mitochondrial dysfunction, what are two signals that tell the cell the mitochondria is dysfunctioning?
- Increased ROS/RNS
- Decreased ATP
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What makes up the apoptosome?
- Cytochrome c
- dATP
- Apaf-1
- Procaspase 9
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What triggers the release of cytochrome-c?
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What activates Procaspase 9?
It cleaves itself causing activation
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What inhibits the release of cytochrome-c?
Bcl-2
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What does XIAP inhibit?
The activity of caspase 9 & caspase 3, inhibiting apotosis
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What does Smac/Diabloe & OmiHtrA2 do?
Inhibits XIAP allowing Caspase 9 and 3 to continue apoptosis
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What does Caspase 3 do after it is active?
Cleaves and degrades ICAD, also Caspases 6 & 7, and the cytoskeleton (causing blebbing)
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Name 4 things p53 can do.
- halt the cell cycle
- stimulate DNA repair
- induce apoptosis
- alters transcription of pro/anti apoptotic genes
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True or false, the cell expressing the Fas Ligand will undergo apoptosis.
False-the cell expressing the Fas RECEPTOR will undergo apoptosis
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Fas is also known as?
CD95
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Fas-L is also known as?
CD95L
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What is on the cytosolic side of the Fas receptor?
FADD (Fas associated death domain) protein
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What does FADD do?
It recruits Procaspase 8 inducing self cleavage and activation
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What dose cFLIP do?
Inhibits the activation of Procapase 8
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What is a DISC?
- death inducing signaling complex
- it is made up of: Fas receptor, FADD, procaspase 8
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What does malignant mean?
tending to infiltrate, metastasize and terminate fatally
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What is it called when a tumor changes from benign to malignant?
Transformation
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What does activation mean?
conversion of a proto-oncogene to an oncogene
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What advantage does abnormality or a genetic defect have?
a replicative advantage over other cells
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What are the 7 hallmarks of cancer?
- 1-genetic instability,
- 2-self-sufficiency in growth signals,
- 3-insensitivity to growth inhibitory signals,
- 4-evasion of apoptosis,
- 5-limitless replicative potential,
- 6-sustained angiogenesis,
- 7-tissue invasion & metastasis
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Explain self-sufficiency in growth signals .
There is an increase in the number of GF receptors and the mutant ones begin to transmit signals without GF
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What types of mutations must occur to acquire an insensitivity to growth inhibitory signals?
mutations blocking receptors for growth inhibitory signals, also mutated p53 and Rb
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What allows for limitless replicative potential?
cancer cells reactivate telomerase which allows the cells to divide indefinitely
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Tumor suppressor genes cause a loss of function mutation, is it dominant or recessive?
Recessive and requires the loss of both alleles
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Oncogenes cause a gain of function mutation is it dominant or recessive?
Dominant and requires the loss of only one allele
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What is nondisjunction?
chromosome loss that occurs during replication when one daughter cell gets both sets of chromosomes and the other cell gets none
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Which receptor is responsible for ~25% of breast cancer?
HER-2
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What is a deletion mutation?
removal of one or more base pairs
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How does HER-2 cause breast cancer?
overexpression of the HER-2 receptor will begin to homodimerize without any ligand binding, thus, activating itself and cause excessive cell proliferation
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How does Herceptin treat breast cancer?
it is an antibody that inactivates the receptor and inhibits the signal that causes the excessive cell proliferation
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What causes chronic myelogenous leukemia?
There is a translocation of Bcr/Abl gene that leads to excessive cell proliferation
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What is overexpressed in B-cell lymphoma?
Bcl-2 (gain of function mutation)
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How does anti-sense therapy work?
it makes a complimentary mRNA strand that will bind to the RNA molecule and both will be degraded, this process could inhibit the overexpression of all the genes that are anti-apoptotic
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What is angiogenesis?
Making of new blood vessels from existing blood vessels
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What causes the onset of angiogenesis?
imbalance between upregulation of pro-angiogenic factors and downregulation of anti-angiogenic factors
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What does VEGF do?
potent stimulus for angiogenesis
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What does VEGF stand for?
vascular endothelial growth factor
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What three things stimulate VEGF?
- hypoxia (HIF binds to VEGF and induces transcription),
- mutations (in p53 results in an overexpression of VEGF), activation (of Ras leads to overexpression)
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What can degrade VEGF?
MMP’s (matrix metalloproteinase) degrade the basement membrane
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What do pericytes do?
they detach from the blood vessel while angiogenesis is occurring then they reattach after the basement membrane is formed
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What are pericytes?
they are cells related to vascular smooth muscle located adjacent to & surround the endothelium
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True or false, soluble VEGF receptors are NOT a natural part of the body?
False, they are a natural part of the body
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What is invasion?
migration of cancer cells break through the barrier that keeps them localized
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What must cancer cells acquire to become malignant and survive in circulation?
the invasive phenotype
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Name the 7 steps of metastasis.
- 1-tumorigenesis,
- 2-angiogenic switch,
- 3-acquire invasive phenotype,
- 4-survival in circulation,
- 5-extravasation & growth at secondary site,
- 6-angiogenesis in secondary tumor,
- 7-evasion of immune response
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What is the angiogenic switch?
the tumor is now secreting VEGF and is stimulating angiogenesis
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What is tumorigenesis?
tumor formation that has acquired many mutations and has a proliferative advantage
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What is this called when the tumor cells kill the immune cells?
immune privilege
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What does HPV (Human papilloma virus) do?
inactivates p53 and Rb
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Are the cells infected with Epstein-Barr virus (EBV) more or less resistant to apoptosis?
Less resistant, there is an increased expression of survival proteins
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Tumor cells with low Fas ____ apoptosis by cytotoxic T cells.
resist
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Tumor cells with FasL expression _____ apoptosis in cytotoxic T cells.
induce
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