Exam 3: Cell Cycle Flashcards
Where do most cells spend 80% of their cycle?
interphase
cells like skeletal muscle and neurons can enter what stage?
quiescence G0, stay in interphase
3 stages of interphase
G1, S, G2
G1
newly formed cell enters stage and begins to express genes to carry out function. Most metabolic function, house keeping stuff of the cell, if differentiated into skeletal muscle cells or cardiac muscle cells neurons will not progress, stay in G1, permanently in G0
S
the synthesis stage in which DNA replication occurs
G2
cell prepares for division
production of proteins (tubulin, kinetochores) needed for division increase
organizational phase
what is the progression through interphase controlled by?
cyclin-dependent kinases and cyclins
cyclin-dependent kinases (cdk)
apoenzymes relatively constant throughout the cell cycle
- take phosphate group off one molecule and put it on another
cyclin
coenzymes that fluctuate during the cell cycle activating cdks
- cyclin and cdk come together to get a holoenzyme, target protein to do phosphorylation
the movement of cells through interphase can be affected by what?
growth factors and tumor suppressors
growth factors
increase rate through interphase
- wound healing
tumor suppressors
decrease or stop progression, can cause apoptosis
- the brakes to a car going down the road
- blebs coming off of it
- cancer apoptosis
G1 to S initially
E2F/DP dimer inactivated by RB
cdk 4 and cdk 6 unbound
cyclin D levels low
G1 to S stimulation
cyclin D level increases
binds to cdk 4 and 6
G1 to S progression
- cyclin D complex phosphorylates RB
- E2F/DP dimer released and active
- E2F/DP transcription factor for cyclin E
- cyclin E forms complex with cdk 2
- cyclin E complex initiates S phase
How does E2F/DP get shut down
RB starts out as a brake, bound to E2F when nothing is going forward the cell is simply in G1
What helps to increase cyclin D?
estrogen receptors
if cell damage, prostaglandins form COX2 pathway which can inc it
S to G2 initially
cyclin E complex moves S phase forward
- E2F levels rise and binding is done to inc cyclin A
Which cyclin outcompetes which?
A outcompetes cyclin E
S to G2 progression
- E2F/DP level rises
- E2F/DP transcription factor for cyclin A
- cyclin A outcompetes cyclin E for cdk 2
- cyclin A forms complex with cdk2
- cyclin A complex phosphorylates E2F
- E2F/DP inactive
- S phase complete
- cyclin A complex initiates G2 phase
what initiates the G2 phase
the cyclin A complex once cyclin A outcompetes cyclin E
G2 to M initially
cyclin A complex phosphorylates cdc 25
phosphatase
it will put on or take off phosphates but does not transfer phosphate groups to another molecule
Cyclin B
constant, increase
its kinase is shut down
dephosphorylate cdk 1
G2 to M progression
- cdc25 activated
- cdc25 dephosphorylates cdk1
- cdk1 forms complex with cyclin B
- cyclin B complex initiates M phase
what is the MPF (M-phase promoting factor)
cdk1 cyclin b complex
Primary System - pRB
- inhibits transcription factor E2F
- acts at onset of cell cycle
- names for research in retinal blastoma
found in all cells
Secondary System - p53
- transcription factor
- inhibited by mdm2
- low p53 promotes p21 expression
- p21 interferes with cdk2 binding (extends S)
- high p53 promotes BAX expression
- BAX promotes apoptosis
when does the secondary system kick in?
only comes in when damage to cell and need extra time
- emergency braking system
- transcription factor you keep quiet until needed (mdm2 is its inhibitor)
when damage to cell, inactivation of mgm2 and what is released
p53
- small amounts of p53 promote p21 which interferes with cdk2 binding - cannot bind cyclin A - cannot finish s phase - gives more time to correct mistakes
if too much damage (p53)
p53 getting too high, get BAX gene which attacks the mitochondria and kills the cell
- since not repairable it kills itself
what happens in cells existing in G0
p16 an inhibitor that binds to cdk 4 preventing activation of E2F
Normal growth factors
- PDGF and EGF increase levels of E2F
- proto-oncogenes regulated
- estrogen increases production of cyclin D
PDGF
platelet derived growth factor for healing
proto-oncogenes
only expressed in diff times in development - early
Abnormal growth factors
- oncogenes unregulated
- upregulation of estrogen receptors
- disruption of tumor suppressors
disruption of tumor suppressors
mutation
infection
chronic inflammation
oncogenes
upregulated proto-oncogenes , turned on when they shouldn’t
- rapid uncontrolled cell growth
upregulation of estrogen receptors
check to see if cancer has increased estrogen receptors
- they can check with estrogen blockers
benign tumor
can still produce adhesion molecules and stay together
hyper-mitotic
fast growing but benign
Polyp
raised form can be either benign or cancerous
Precancerous
some morphological changes from cells of origin, but still adheres together
Cancer
morphological changes obvious, not adhering
Stage 0
-caught at earliest, still in tissue where it formed
0 small not invasive tumor
stage 1
small and invasive to immediate surrounding tissue
difference between stage 1 and stage 2?
stage 2 is not worse, it is done by size, so stage 2 is larger in mm than stage 1
stage 2`
large and invasive to immediate surrounding tissue
stage 3
invasive to local lymph nodes
- if find in lymph node you know the cancer cells changed enough to no longer recognize cells they came from, metastasizing
stage 4
- invasive to distant tissue
- metastasized beyond lymph nodes
Application: Pharmacology Targets for Cancer
- cyclin D dysregulation can lead to progression of types of cancer
- goes through too fast, can make mistakes
Application: Pharm targets for cancer
How do the following targets lead to a dec in cyclin D?
kinase inhibitors stop the initial kinase from binding cyclin D
- block estrogen
radiation, immunotherapy go after cyclin D
- competitive binding inhibitors prevent binding of cdk4 and cdk 6 which blocks cyclin D from forming its complex
Application: pharm in cancer
how would this affect target cell’s cycle of development?
cdk inhibitors to inhibit cdk 2 - cannot enter the S phase
Application Ulcerative Colitis
Explain why ulcerative colitis is associated with an inc risk f colon cancer?
has chronic inflammation inc the risk, does not cause cancer
- release of signaling inc the cell cycle, setting up environment where if mistakes happen you could be at risk for cancer
Why would someone who has irrital bowel syndrome can have similar discomfort but not an increased cancer risk?
the inflammation would draw growth factors from mitosis
- lower risk of cancer with anti inflammatory drugs
Application: Cancer
mutation in BRCA1 gene affects binding of RB to E2F/DP
How does BRCA1 normally enhance binding?
slowing the phosphorylation of the complex
- slows release of transcription factor slowing down cell cycle, enhancing primary braking system RB
BRCA 1 mutation compared to defective p53
similar: both phases S phase effected - inc risk of errors to go through for both
- differences: p53 slows down S phase (if defect you would not be able to slow it down)
- in BRCA defect S phase would speed up, less time to avoid mutations
- defect in p53 lose ability to do apoptosis
Application: Triple Negative Breast Cancer
triple negative cells have no marker, no estrogen or hormone receptors, no epidermal growth factor receptors
challenges for triple negative breast cancers?
nothing to inhibit - no receptors to block.
- you cut out what you can find, use chemo and radiation
HER2
forms heterodimer as normal receptor
- when binds epidermal growth factor triggers cell to put out more cyclin D
- constantly going through mitosis without signal
Application: Cancer and Viruses
2 ways HPV increases risk of cancer
- HPV gene 6 inactivates p53
- HPV gene E7 inactivates pRB
Application: explain how inactivating p3 and pRB would effect the cell cycle and inc cancer risk?
inactivating p53: cannot do apoptosis, take out potentially cancerous cells
inactivating pRB: cannot end S phase - replicating too fast causing mistakes
What does HPV take out?
both braking systems primary (pRB) and secondary (p53)
speeds up cell cycle can not slow down if mistakes
