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

Ch. 8: RB and Cell Cycle Flashcards

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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
Q

Which CDK and cyclin do you predict to be important
during the R check point?

A

CDK4/6

26
Q

What regulates cyclin D1 heavily?

A

extracellular inputs
(Wnt, cytokine, hedgehog, other ligands)

27
Q

What does growth factor RTK do to D1?

A

RTK activation ultimately increases the transcription of D1

28
Q

What does cell attachment to the ECM do to cyclin D1?

A

Cyclin D1 txn is also regulated by cell
attachment to the ECM (anchorage dependence growth)

29
Q

Why does D1 have to be heavily regulated?

A

D1 needs to be heavily
regulated because once CDK4/6 is active, cell division WILL occur

30
Q

Cyclin-CDK complexes are regulated by…

A

inhibitors

Different terminology over the years
* Originally- INKs (inhibitors of CDK4)
* Currently- CKI (cyclin kinase inhibitors

31
Q

Function of CKI

A

inhibit Cyclin-CDK formation
and function

32
Q

P21CIP

A

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
Q

What inhibits CDKIs

A

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
Q

When in the cell cycles is Db de-phosphorylated?

A

during G0

35
Q

When in the cell cycles is Db mono-phosphorylated?

A

during the G1 stage of the cell cycle up until the R checkpoint

36
Q

When in the cell cycles is Db hyper-phosphorylated?

A

after the R checkpoint and at all other stages of the cell cycle

37
Q

What is RB important for?

A

for entry past the R checkpoint

38
Q

Viral E7 protein of HPV binds to RB and inhibits…

A

its function and targets it for proteasomal degradation

39
Q

RB and TP53 usually inhibit…

A

cell proliferation and
ensures cell division is
tightly regulated (it only
occurs when necessary)

40
Q

Viral proteins bind to RB
and TP53 proteins, this
allows for…

A

for the transcription
of genes that promote cell
division (proliferation)

41
Q

What inhibits E2F TF’s? how?

A

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
Q

what are E2F pocket proteins?

A

are transcription
factors (TFs) that regulate genes that cause transition from G1 to S phase

43
Q

What prevents RB from binding to E2F?

A

hyper-phosphorylation

44
Q

What happens if RB cant bind to E2F?

A
  • 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
Q

What controls RB phosphorylation?

A
  • 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
Q

Determine which version of RB is present in each part
of the diagram below labelled in purple
(slide 32)

A

1- de-phosphorylated
2- mono-phosphorylated
3- hyper-phosphorylated
4- hyper-phosphorylated
5- hyper-phosphorylated
6- hyper-phosphorylated

47
Q

How does GF-RTK signaling induce cell division?

A

Growth factors -> RTK receptors -> Ras -> Cyclin D1 and E -> inactivation of RB -> activation of E2F’s -> S-phase entry

48
Q

RB pathway Review

A
  • 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
Q

What does E6 and E7 inactivate?

A

TP53 and RB (tumor suppressors)

50
Q

What does E6 and E7 do in HPV?

A

they integrate into the host genome and are expressed at high levels

51
Q

MYC transcription factor from previous lectures

A
  • 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
Q

General MYC knowledge

A
  • 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
Q

Deregulated MYC is
sufficient to…

A

drive cell proliferation in the absence of growth factors because it has many downstream effects that promote cell cycle progression

54
Q

How does MYC promotes cell cycle progression
through the activation
of D2 and CDK4

A
  • MYC/MAX promote the txn of D2 and CDK4
  • Active CyclinD2-CDK4 complexes mono-
    phosphorylate RB to drive progression through G1
55
Q

How does MYC promotes cell cycle progression
through the activation
of Cul1

A
  • 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
Q

How does MYC promotes cell cycle progression
through the inhibition
of p15

A
  • 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
Q

How does MYC promotes cell cycle progression
through the activation
of E2F

A
  • MYC/MAX promote the txn of E2F transcription factors
  • Further drives the progression of cells
    past the R point
58
Q

In summation, deregulated MYC…

A

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
Q

The RB pathway is dysregulated in…

A

most if not all cancers

60
Q

About the RB pathway

A
  • 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
Q

Perturbation of R-point transition in human tumors:

A

Molecules in red are hyperactive in some cancers
Molecules in blue are in activated in some cancers

62
Q

Active TGFB signaling inhibits…

A

cell division
- Because p15 is an inhibitor of CyclinD/CDK4, activated TGFB signaling causes inhibition of G1 cell cycle
progression

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