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69 Cards in this Set
- Front
- Back
Interphase
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all cell cycle phases EXCEPT mitosis (Go, G1, S, G2)
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Go phase
-duration -event |
-days/mos/years
-metabolically active but NOT cycling -low protein expression -receptive to mitogens *induced by contact inhib, growth fact w/d |
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G1 phase
-duration -event(s) |
- 12-24hrs
-lg incr in cell size -receptive to extracell growth factors -chroms prepped for duplic *variability in fast/slow growing cells |
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S phase
-duration -event(s) |
-8 hrs
-chroms duplicated *sensitive to DNA damage *cancer cells spend more time in S-phase --> why radiation Tx works |
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G2 phase
-duration -event(s) |
-some addt'l cell size increase
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Mitosis
-duration -events |
-1 hr total
-split into two daughter cells |
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Mitosis: prophase
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-Chroms condense
-nuc env breakdown |
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Mitosis: prometaphase
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-spindle assembly
-chrom congression (start to align on spindle) |
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Mitosis: metaphase
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-chrom align
-chrom attach to spindle |
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Mitosis: anaphase
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-chrom sep
-spindle disassembly *sensitive to alignment defects |
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Mitosis: telophase
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-chrom decondense
-nuc env assembly |
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Mitosis: cytokinesis
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-divide cytoplasm btwn 2 daughter cells
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Genome instability causes
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-replic errors or DNA repair defects (S phase)
-chrom segreg errors (M) |
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Mitosis promoting factor (MPF)
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Cdk1/CyclinB
-Cdk1 = Ser/Thr kinase -substrates = LaminA, histones (+Pi = promote mitosis) -levels of Cdk DON'T change over cell cycle; CYCLIN levels change |
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Mitotic index
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-how many cells are in mitosis on the microscope field
-higher % = more likely to be cancerous (spend more time in M b/c cycling faster & make more errors) |
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Mitosis Cdk/Cyclin pair
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Cdk1/CyclinB
(Cdk1 = cdc2) |
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S phase Cdk/Cyclin pair
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Cdk2/Cyclin A1/A2
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G1-to-S transition Cdk/Cyclin pair
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Cdk2/Cyclin E1,2
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Cyclin D
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ONLY cyclin that responds to extracellular growth factors
(Ras/Raf/MAPK: increase transcription PI3K pathway: +Pi makes Cdk/CycD more stable complex) --> helps cell go from Go to G1 CycD/Cdk4,6 inhibs Rb, so E2F active --> S phase genes on |
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Rb protein
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-inhibits E2F (so inhib S phase genes)
-bound to HDAC (histone deacetyl) -CycD/Cdk4,6 inhibs Rb binding to E2F (Cdk4,6 phosphorylates Rb= weakens binding to E2F) |
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E2F protein
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-controls expression of S phase genes (directly binds to DNA)
-inhib by Rb |
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HDAC (histone deacetylase)
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-removes acetyls from histones
-fewer acetyls = less accessible DNA (more compact) -bound with Rb to E2F to inhib S phase genes |
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Tumor suppressors
-mech of fcn -examples |
-inhibit cell cycle progression
-Rb, p53, p16, RAF |
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Proto-oncogenes
-mech of fcn -examples |
-stimulate cell cycle progression
-Cyclin D1, Mdm2, c-myc, Ras |
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Oncogene
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mutated proto-oncogene
gain of fcn/overexpression --> cancer |
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Effect of ↑ Cyclin D1 & ↓ Rb
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↑ cell cycle progression --> cancer
↑ CycD = ↓ inhib of Rb = E2F active ↓ Rb = less inhib of E2F => Sphase genes made |
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C-myc
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transcription factor
promotes cell growth (↑ mass) -MAPK & PI3K pathways promote c-myc activity --> prot synth genes made --> Go-G1-S |
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Effect of ↑ c-myc & ↓ Rb
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Cancer!
c-myc = more prot synth genes made Rb del means E2F active & Go to G1 trans promoted |
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S-phase promoting factor
-mechs of fcn |
CyclinE/Cdk2
-promotes DNA replic via +Pi to helicase -phosphorylates Rb so ACTIVE (E2F suppr - no more S genes made- not needed) -blocks new licensing (G1/S) |
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Cak
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Cyclin activating kinase
-Pi on T160 of Cdk's activation loop |
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Cdk4,6 inhibitors
-ID -mech of fcn |
p16(INK4) family:
-p15, p16, p18, p19 -competitive inhibition (bind at same spot as cyclin D) |
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how does p16 alteration ==> cancer
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-↓ p16 = ↑ CycD = ↓ inhib of Rb = E2F active--> S phase genes --> cell prolif
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Cdk1, 2 inhibitors
-ID -mech of fcn |
p27 family:
-p21, p27, p57 -bind to catalytic cleft of Cyc/Cdk = trimeric -affects CycA,E/Cdk2 & CycB/Cdk1 |
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How do cells go from Go--> G1?
-mech |
-Go= high levels p27, p16, p21 & low levels CycE/Cdk2
-cell receives signal--> ↑ CycE -(G1/S) some CycE/Cdk2 Pi's p27 -p27-Pi recog by Spk2--> Cul1 recruited -Cul1 ubiquinates p27-Pi-->degrad -(S) CycE/Cdk2 self-Pi's for recog by Cul1, ubiq--> degrad |
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p27 -/- mice: larger or smaller than WT?
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larger: more cells in body b/c p27 doesn't inhib CycE,A/Cdk2 or Cdk1
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Skp2 -/- mice: larger or smaller than WT?
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smaller: Skp2 levels low = higer p27 --> more CyclinE/Cdk2 inhib --> CyclinE/Cdk2 inactive
suppressed cell prolif |
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Wee1 protein
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-kinase that Pi's CyclinB/Cdk1 at Y15 site (NOT on activ loop) --> Cyc/Cdk inactive
-when Wee1 inactive, cell goes thru mitosis too quickly = cells too small |
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pre-mitosis DNA damage pathway
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detector --> (+) ATR kinase --> (+) Chk 1 kinase --> (-) Cdc25
= CycB/Cdk1 inactive ==> nuc disassembly & chrom condens'n |
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Cdc25 protein
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-phosphatase
-does reverse of Wee1 -removes Pi on CycB/Cdk1 so Cyc/Cdk is active -inhib by Chk1 kinase |
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DNA damage inhibition of Cdk1 activity (2 mechs)
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-inactivation of phosphatase (Cdc25: detector/ATR kinase/Chk1 kinase/Cdc25)
-activation of p53 (--> more p21 so more inhib of Cyc/Cdk) |
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p53 protein
-general fcn -activators -inhibitors |
-cell cycle prolif inhibitor: activates p21 (which inhibs Cdk1 &2 = complex w/ Cdk & cycB, E/A)
-induced by stressors--> +Pi = active -->cell cycle arrest, DNA repair, senescence, apoptosis -activ by kinases; Pi weakens binding w/ Mdm2 -Mdm2 inhibits (ubiq ligase) [ARF inhib Mdm2 = ↑p53] |
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Mdm2 protein
-mech of fcn -activators -inhibitors |
-ubiquitin ligase; inhibs p53 when bound to it (via ubq'n)
-Mdm2 default to be bound to p53? -ARF inhibs |
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protein degradation regulation mechanisms (4)
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-substrate phosphorylation to induce E3 ubiq ligase binding
-regulate activity of E3 itself -substrate phosphorylation to block -regulate expression of E3 |
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Cohesin protein
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deposited on chroms as replic occurs
-holds sister chroms together until anaphase -removed by separase |
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anaphase promoting complex (APC)
-mech of fcn -inhibitors -activators |
-ubiqs CycB & securin for degrad (which makes separase active)
-inhib when sis chroms NOT attached to spindle [detector-kinase-effector pathway] -activ'd when detector leaves (b/c finds sis chroms attch'd to spindle) |
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Securin protein
-mech of fcn -inhibs -activs |
-inhibits separase; when degrad, separase active
-inhib (degrad) when Ubq'd by APC for degrad -activ when sis chroms NOT attached to spindle |
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Separase
-mech of fcn -inhibs -activs |
-removes cohesins from btwn sis chroms--> anaphase
-inhib when bound to securin -activ when securin degrad (Ubq'd by APC when sis chrom attch'd to spindle) |
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Taxol, vinblastine fcn
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-cancer Tx
-make difficult for cells to go through mitosis -highly toxic |
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Tumor-causing viruses
-RNA mech -DNA mech |
-RNA: integrates into genome, carry or activate oncogenes
-DNA: does NOT integrate, carry viral oncogenes; if accidentally integr, viral prot constit expressed |
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HPV
-viral type -general fcn of cancer causing |
-DNA
-makes host cell move into S phase so can use DNA replic machinery for own protein expression purposes -integr of fragment w/ E6 & E7 genes is worst-- knock out two tumor suppressor elements (p53 & Rb) |
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HPV E6 gene fcn
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-E6 binds to p53 & induces its deregulation
(E6AP is E3 ubiq ligase) |
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HPV E7 gene fcn
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-binds to Rb & blocks Rb intrxn w/ E2F --> E2F active --> Sphase
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Examples of mutations --> cancer
-describe mech of fcn 1) ↑Mdm2 ; ↓ Rb 2) ↑CyclinD ; ↓ p53 3) ↓ p16 ; ↓ ARF * |
1) ↑Mdm2 = ↓ p53; ↓ Rb= ↑E2F activity
2) ↑CyclinD=Go-G1 trans ; ↓ p53 = ↓p21=Cyc/Cdk remains active 3) ↓ p16 = ↑ CycD = ↓ inhib of Rb = E2F active ; ↓ ARF= ↓ inhib Mdm2 = ↓p53 *p16 & ARF encoded by same gene; alt reading frame |
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ARF-Mdm2-p53 pathway: which changes cause cancer?
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↓ ARF ; ↑ Mdm2 ; ↓ p53 = cancer prone… one hit enough
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Nutlins
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molecs that bind Mdm2 & compete for p53 intrxn
-Useful for cancers where Mdm2 is overexpressed (too much degrad of p53) |
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Hallmarks of cancer
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- Resisting cell death
- Sustaining prolif signal - Evading growth suppressors - Activating invasion & metastasis - Enabling replicative immortality - Inducing angiogenesis |
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Cancer contributors: abnormal ↑ in cell #
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=more cell divisions/less apoptosis
Eg: loss of Cdk control: prob w/ upstream signaling or downstream core regulator problems |
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Cancer contributors: Genetic instability
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cell pop becomes increasingly heterogeneous
○ Loss of checkpoint control ○ Loss of DNA repair efficiency ○ Loss of chrom segreg control |
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Cancer contributors: Changes in cell adhesion & migration
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b/c of changes in integrin signaling, etc
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Cancer contributors: - Induction of angiogenesis (new blood vessels)
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○ Stim of VEGF receptor in tumors (vasc endothel growth fac)
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Cancer contributors: mutation in growth factor signaling pathways
3 overall ways to have errors |
1) Growth factor over pdc'n
2) RTK overexpression (receptor TyrKin) 3) Ras activation (or player downstream of this) |
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Receptor Tyrosine Kinase (RTK)
2 major signaling pathways -ultimate effect on ___ |
1) Ras-Raf-MAPKK-MAPK
2) PI3K **both work to ↑ CyclinD & C-myc (promote cell prolif) |
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Cancer contrib: Growth factor-independent signaling- 3 ways
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-Mutation of Ras causes it to be stuck in GTP (active) form
-Receptor over-production; sheer mass action -One of players in pathway (after receptor) is mutated so constit active (eg: Raf) |
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Philadelphia chromosome
-mutation -effect |
-Reciprocal translocation btwn chroms 9 & 22 in chronic myelogenous leukemia = new oncogene (BCR-ABL)
○ ABL: non-receptor TyrKin like Src?. Mut moved one of domains --> constit active kinase ○ BCR: signaling protein; when fuse BCR to ABL, disrupts auto-inhib domain of ABL --> constit active OVERALL: Activates Ras & PI3K pathways b/c can put Pi on Tyr when not supposed to |
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Gleevec
-how fcn |
-small-molec inhib. of TyrKin specific to BCR-ABL (Philadel) protein that not usually in normal cells (so few side effects as Tx b/c only targeted cancerous cells)
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Mutations/deletions that cause cancer: Rb
-what mutation affects |
-no Rb = E2F active --> transcription of S-phase genes
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Mutations/deletions that cause cancer: p16INK4
-what mutation affects |
-Cdk 4 & 6 inhib;
-p16 family competes for same binding spot as CyclinD |
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Mutations/deletions that cause cancer: p27 family
-what mutation affects |
-Inhib Cdk 1 & 2
-trimeric: binds btwn Cdk & Cyclins (B, E/A) |
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Mutations/deletions that cause cancer: DNA damage chkpts
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-BRCA1
-ATM -Chk1/Chk2 -p14ARF -p53 |