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NIH definition of cancer
- 1) abnormal cells divide without control
- and
- 2) are able to invade other tissues
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transformed cells invade other tissues
metastasis
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6 hallmarks of cancer
- 1) sustaining proliferative signaling
- 2) evading growth suppressors
- 3) activating invasion and metastasis
- 4) enabling replicative immortality
- 5) inducing angiogenesis
- 6) resisting cell death
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genes that promote cancer
oncogenes
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what happens to oncogenes that make them contribute to the cancer phenotype?
- become permanently active or
- are overexpressed
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typical jobs oncogenes perform (2)
- 1) cell growth circuitry
- 2) factors that promote cellular survival/migration
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tumor suppressor genes
- mutated/deleted in cancer cells
- sensors of cell damage or genes that promote apoptosis
- "gate keepers"
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examples of tumor suppressor genes (2)
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when cells have reached their doubling limit (plateau)
or
the loss of the proliferative ability of a cell associated with age
senescence
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PDM
population doubling mean
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what types of damage contributes to senescence? (2)
- 1) oxidative damage
- 2) DNA damage
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cells grown in ____ (normal/high/low) oxygen reach senescence sooner than cells grown in _____ (normal/high/low) oxygen.
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what types of DNA damage can trigger senescence? (2)
- 1) loss of telomeres
- 2) triggering DNA damage checkpoint in cell cycle
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"replication clock" that lies at the end of chromosomes
telomere
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loop structures that are several thousand bp's long, that shield DNA ends so chromosomes don't fuse together
telomeres
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characteristics of telomere sequence (2)
- 1) repetitive
- 2) consists of several thousand repeats of a 6bp sequence
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how cell division is limited in a normal cell
RNA primer that starts polymerase copying is degraded during each replication
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when the cell loses enough telomere sequence, and can't protect chromosome ends, but continues to try to divide
Crisis
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effect of Crisis
unprotected DNA end can fuse with other ends, causing massive damage: the breakage-fusion-bridge cycle
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enzyme that copies and extends the telomere
telomerase
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hTERT
- human telomerase reverse transcriptase
- multiple subunits contained in telomerase
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what occurs when hTERT is introduced into cells just entering in the crisis stage
- allows cells to continue to grow
- -> hTERT is growth limiting factor
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expressed in cancer cells to evade crisis & divide forever
telomerase
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2 mechanisms by which cell division is strictly limited
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breaks the circuit between growth factor receptors and proliferation
senescence
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result of Crisis
cells lose telomeres, and undergo massive DNA rearrangements and usually die from apoptosis
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stage in which cells are not dividing
G0
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stage in which cell is preparing for cell division
G1
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cell remains responsive to both inducing and inhibiting signals until this point
restriction point
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after the restriction point, the cell will not respond to these signals
inhibitory signals
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G1/S checkpoint
- just before DNA synthesis
- cell checks itself for damage
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phase during which the cell copies its DNA
S phase
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phase during which the cell prepares for cell division
G2
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phase during which the cell undergoes mitosis
M phase
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what occurs at each checkpoint in the cell cycle?
the cell makes sure that its DNA is not damaged before proceeding
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p53 characteristics (3)
- 1) central sensor of damage
- 2) moves cell into apoptosis if genome can't be repaired
- 3) is a TF - promotes repair or apoptosis
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gene that MUST be mutated/deleted for transformation to cancer
p53
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4 responses by p53
- 1) cell cycle arrest
- 2) DNA repair
- 3) block of angiogenesis
- 4) apoptosis
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proteins which promote the cell cycle (most found in G1)
cyclins
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what cyclins bind to
CDKs (cyclin dependent kinases)
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most important CDK complex inhbitor
Rb (retinoblastoma gene)
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what all regulators of G1 are focused on activating/repressing
Rb
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when the first phosphate gets put on Rb, the cell has entered ___.
G1
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Rb at the end of mitosis
completely dephosphorylated
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what CDK complexes are focused on
phosphorylated Rb
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CDK complex that begins the process of Rb phosphorylation
CyclinD/CDK4
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CDK complex that adds multiple phosphates to Rb
CyclinE/CDK2
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when the cell cycle can no longer be shut down by an external signal
once Rb becomes hyperphosphorylated and the restriction point has passed
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E2F (4)
- 1) transcription factors
- 2) sequestered by Rb in early G1
- 3) released by Rb when hyperphosphorylated
- 4) promote transcription of genes which will drive cell to S phase
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gatekeeper that keeps cells from entering cell cycle by sequestering TF's needed to transcribe essential cell cycle proteins
Rb
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external growth inhibitory factor
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what is the cell cycle driven by?
transcription factors of the E2F family
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tumors that reach a certain size and then stop
benign tumors
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tumors that invade vascular tissue and enter the blood
metastasized tumors
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for many cancers, what does the risk come mostly from?
environment
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