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Cancer Biology > Ch. 8: RB and Cell Cycle > Flashcards

Ch. 8: RB and Cell Cycle Flashcards

1
Q

Cell cycle

A

map of all the steps
that occur within a cell from the moment it is created from one cell division to the end of the next round of cell division

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2
Q

Contact dependent growth

A

If you put human cells in culture they will continuously divide until they run into each other

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3
Q

Mitosis

A

Process of cell division that includes 1. equal division
of chromosomes between 2 daughter cells 2. the physical
splitting of 1 cell into 2 daughter cells. (~1 hour)

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4
Q

Stages of mitosis

A
  • prophase
  • prometaphase
  • metaphase
  • anaphase
  • telophase
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5
Q

Cell growth and example

A

cells are getting physically bigger in preparation for cell division
- Ex: Doubling macromolecules and organelles- (lipids- membrane, proteins- ribosomes, carbs- modifications on cell proteins), organelles-endoplasmic reticulum

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6
Q

Synthesis

A

Cells are duplicating their
DNA in preparation of cell division (DNA polymerase) (varies)

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7
Q

Stages of cell cycle

A
  • mitosis
  • G0
  • G1
  • synthesis
  • G2
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8
Q

G0 (Temporary and permanent)

A

Cells make decision not to divide at that moment in time. (Can occur during
G1 as well.)
* temporary- quiescent occurs at G0
* permanent- senescent occurs at G1/2

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9
Q

Gap 1

A

Gap between G0 and Synthesis (~6-8 hours)

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10
Q

Gap 2

A

Gap between Synthesis and Mitosis
(~3-5 hours)

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11
Q

Interphase

A

G0, G1, S, and G2
(part of the cell cycle not containing mitosis)

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12
Q

What would happen if chromosomes are not duplicated properly?

A
  • potential transformation
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13
Q

What would happen if division does not occur properly and each daughter cell does not get exactly 2 copies of every chromosome?

A
  • If 2+ copies, proto-oncogene can become an oncogene
  • if 2- copies, tumor suppressor genes could cause transformation
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14
Q

In a way, proteins/molecular complexes involved in the cell cycle are tumor
suppressors because…

A

loss of them would
lead to situations that promote cancer

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15
Q

Very important for the cell to have # of quality control steps along the cell cycle to
ensure…

A

cells are ready to go on to the next step. (Alleviates potential for cancer).

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16
Q

checkpoints

A

control mechanism to ensure the next step in a process does not proceed
until necessary prerequisites have been fulfilled.

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17
Q

R point

A

The most critical decision-making occurs whether
to continue dividing or exit the cell cycle (and
enter G0). This occurs during G1 up to the R point.
Cells are listening to their neighbors

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18
Q

Example of issue at a check point

A
  • DNA damage G1 to 2
  • DNA damage S to G2
  • entrance to M is blocked if replication is not completed
  • anaphase is blocked if not attached to the mitotic spindle
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19
Q

the most critical checkpoint regarding the onset of cancer (and example)

A

the R point

  • Ex- Anchorage dependent growth: ensure cells are properly attached to ECM (via integrins) before S can occur. If cells are not attached at all initiates self-destruction (apoptosis)
  • Anchorage independent growth- property of transformed cells- involves oncogenes (such as RAS and SRC) tricking the cell into thinking it is properly anchored
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20
Q

How do cell cycle checkpoints work on a
molecular level?

A
  • CDKs?
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21
Q

Cyclin dependent Kinases

A
  • CDK’s are usually present throughout the cell cycle.
  • Each CDK phosphorylates and activates a set of target genes involved in a specific
    stage of the cell cycle
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22
Q

What regulates CDK activity?

A

the presence of cyclins

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23
Q

cyclins

A

proteins that bind to CDK’s and activate them (turn them on)
1. Activate their kinase activity
2. Help them find the right substrates to phosphorylate

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24
Q

When are cyclins present/active?

A

at precise times in the cell cycle

Ex- CyclinB is only present at the M stage, therefore CDK1 is only active during this stage

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25
Which CDK and cyclin do you predict to be important during the R check point?
CDK4/6
26
What regulates cyclin D1 heavily?
extracellular inputs (Wnt, cytokine, hedgehog, other ligands)
27
What does growth factor RTK do to D1?
RTK activation ultimately increases the transcription of D1
28
What does cell attachment to the ECM do to cyclin D1?
Cyclin D1 txn is also regulated by cell attachment to the ECM (anchorage dependence growth)
29
Why does D1 have to be heavily regulated?
D1 needs to be heavily regulated because once CDK4/6 is active, cell division WILL occur
30
Cyclin-CDK complexes are regulated by...
inhibitors Different terminology over the years * Originally- INKs (inhibitors of CDK4) * Currently- CKI (cyclin kinase inhibitors
31
Function of CKI
inhibit Cyclin-CDK formation and function
32
P21CIP
cyclin dependent kinase inhibitor * Levels of p21CIP increase in a cell in response to cellular stresses including DNA damage * Will shut down E-CDK2/A-CDK2 complexes so that the cell cycle will stop until DNA is repaired
33
What inhibits CDKIs
growth promoting signals * Mitogens (such as growth factors)- activate RTK’s and subsequent activation of AKT * Active AKT phosphorylates p21Cip1 and p27Kip1 in the nucleus which causes them to be exported to the cytoplasm * Lack of CDK inhibitors in the nucleus causes subsequent activation of cyclin-CDK complexes in the nucleus * Promotes progression of the cell cycle (cell division)
34
When in the cell cycles is Db de-phosphorylated?
during G0
35
When in the cell cycles is Db mono-phosphorylated?
during the G1 stage of the cell cycle up until the R checkpoint
36
When in the cell cycles is Db hyper-phosphorylated?
after the R checkpoint and at all other stages of the cell cycle
37
What is RB important for?
for entry past the R checkpoint
38
Viral E7 protein of HPV binds to RB and inhibits...
its function and targets it for proteasomal degradation
39
RB and TP53 usually inhibit...
cell proliferation and ensures cell division is tightly regulated (it only occurs when necessary)
40
Viral proteins bind to RB and TP53 proteins, this allows for...
for the transcription of genes that promote cell division (proliferation)
41
What inhibits E2F TF's? how?
De-phosphorylated and mono-phosphorylated (active) RB Active RB (de or monophosphorylated) binds to E2F pocket proteins and recruits HDAC which changes the chromatin in such a way that inhibits RNA polymerase (txn)
42
what are E2F pocket proteins?
are transcription factors (TFs) that regulate genes that cause transition from G1 to S phase
43
What prevents RB from binding to E2F?
hyper-phosphorylation
44
What happens if RB cant bind to E2F?
* Thus histone acetylases can bind to E2F * This changes the chromatin in such a way that now RNA polymerase can bind these genes and txn is activated * Reminder- these genes cause transition from G1 to S phase (transition past the R point) (~500 genes)
45
What controls RB phosphorylation?
- de-phosphorylation: protein phosphatases - mono-phosphorylation: CDK4/6 and cyclin D (active G0 CDK's) - hyper-phosphorylation: CDK2 and cyclin E (active G0 to S1 CDK)
46
Determine which version of RB is present in each part of the diagram below labelled in purple (slide 32)
1- de-phosphorylated 2- mono-phosphorylated 3- hyper-phosphorylated 4- hyper-phosphorylated 5- hyper-phosphorylated 6- hyper-phosphorylated
47
How does GF-RTK signaling induce cell division?
Growth factors -> RTK receptors -> Ras -> Cyclin D1 and E -> inactivation of RB -> activation of E2F’s -> S-phase entry
48
RB pathway Review
* Un-phosphorylated RB puts cells in G0 (out of the cell cycle) * RB is monophosphorylated by active CyclinD-CDK4/6 during the progression of G1 * RB is hyperphosphorylated by active CyclinE—CDK2 during the end of G1 and beginning of S (R checkpoint) * Once RB is hyperphosphorylated, it no longer binds E2F TF’s * Active E2F activates the txn of genes involved in S phase, ex- DNA polymerase
49
What does E6 and E7 inactivate?
TP53 and RB (tumor suppressors)
50
What does E6 and E7 do in HPV?
they integrate into the host genome and are expressed at high levels
51
MYC transcription factor from previous lectures
* Tumor virus lecture- -> B-cell lymphomas are induced by ALV integration in front of the MYC locus in the host genome (slow transforming retrovirus) -> Increases the gene expression of MYC * Oncogene lecture- -> Burkitts lymphoma a chromosomal translocation causes MYC to be under the control of an active immunoglobulin gene promoter
52
General MYC knowledge
* More than 70% of human tumors overexpress MYC or one of its orthologs * Normal function- growth promoting TF (transcription factor) * Active when heterodimerizes with MAX TF * Growth factors cause increase in cellular levels of MYC
53
Deregulated MYC is sufficient to...
drive cell proliferation in the absence of growth factors because it has many downstream effects that promote cell cycle progression
54
How does MYC promotes cell cycle progression through the activation of D2 and CDK4
* MYC/MAX promote the txn of D2 and CDK4 * Active CyclinD2-CDK4 complexes mono- phosphorylate RB to drive progression through G1
55
How does MYC promotes cell cycle progression through the activation of Cul1
* MYC/MAX promote the txn of D2 and CDK4 * CUL1 helps degrade p27 through ubiquitylation * p27 is normally an inhibitor of CyclinE- CDK2 complexes (which normally phosphorylate and inactivate RB) * End Result- Inactivation of RB, further drives cells to progress through R point
56
How does MYC promotes cell cycle progression through the inhibition of p15
* MYC/MIZ-1 inhibits the txn of p15 * p15 is normally an inhibitor of active CyclinD2-CDK4 complexes * End result- increased activity of cyclinD1- CDK4 which mono-phosphorylate RB and drive progression through G1
57
How does MYC promotes cell cycle progression through the activation of E2F
* MYC/MAX promote the txn of E2F transcription factors * Further drives the progression of cells past the R point
58
In summation, deregulated MYC...
Deregulated MYC is sufficient to drive cell proliferation in the absence of growth factors because it has many downstream effects that promote cell cycle progression
59
The RB pathway is dysregulated in...
most if not all cancers
60
About the RB pathway
* Major characteristic of cancers- uncontrolled cell growth * Since RB control of the R checkpoint is what controls if a cell will divide or not * Makes sense RB is dysregulated in so many cancers * RB pathway can be dysregulated in many ways -> (Perturbation of R-point transition in human tumors)
61
Perturbation of R-point transition in human tumors:
Molecules in red are hyperactive in some cancers Molecules in blue are in activated in some cancers
62
Active TGFB signaling inhibits...
cell division - Because p15 is an inhibitor of CyclinD/CDK4, activated TGFB signaling causes inhibition of G1 cell cycle progression

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