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Tumour > Lectures 3-4 > Flashcards

Lectures 3-4 Flashcards

1
Q

Types of inherited single gene defects

A

-Retinoblastoma, a childhood eye cancer (Rb)
-Li-Fraumeni syndrome (p53)
-BRCA1
-2 predisposition to breast and ovarian cancer (APC)

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2
Q

Two forms of Retinoblastoma

A

-Familial (Hereditary): Multiple tumors, affecting both eyes, early onset, 6x increased cancer risk.
-Sporadic (Non-hereditary): Single tumor, affecting one eye, later onset.

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3
Q

Phases of cell cycle:

A

-G1
-S
-G2
-M
-G0

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4
Q

G1:

A

Cell make decisions about growth versus quiescence

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5
Q

S phase:

A

DNA is synthesized

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6
Q

G2:

A

Making sure all the DNA is replicated with fidelity

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7
Q

M Phase:

A

-2 new cells are made through the division of the genetic material
-mitosis (prophase, prometaphase, metaphase, anaphase, telophase) and cytokinesis

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8
Q

G0:

A

Resting, nonproliferative state of cells that have withdrawn from the active cell cycle

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9
Q

What features do checkpoints have:

A

-Allow internal feedback control
-Allow control from external stimuli

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10
Q

Types of cell cycle checkpoints:

A

-G1/S (determines if DNA synthesis can begin)
-Intra-S and G2/M (Prevents the replication of damaged DNA until repaired)
-Spindle Checkpoint (ensures chromosomes are aligned correctly to spindle. If not mitotic arrest doesn’t proceed to Anaphase)

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11
Q

Progression to S phase depends on?

A

The presence of growth factors in the G1 phase up until the restriction point.

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12
Q

What is the restriction point.

A

A checkpoint where a cell must make the decision of whether to proceed to S or to enter G0. At this point growth factors no longer influence progression.

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13
Q

CDK Inhibitors:

A

-INK4/CDKN2 (p16, p15, p18, p19).
-CIP/KIP/CDKN1 (p21cip1, p27kip1)

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14
Q

How does INK4 inhibit?

A

They bind to CDK4/6 which prevents it from binding to cyclin D

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15
Q

How does the CIP/KIP/CDKN1 inhibit?

A

They can inhibit all of the other cyclin-CDK complexes by blocking their ATP binding site.

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16
Q

What is CAK

A

-Stand for CDK activating kinases.
-Work by phosphorylating the activation loops.

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17
Q

What is CD25

A

It is a class of phosphates that remove inhibitory phosphorylation’s that affect CDK2

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18
Q

How are cyclin Ds activated?

A

By growth factors causing a signaling cascade resulting in transcription factor AP-1 which regulates key cyclins.

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19
Q

How is cyclin E/CDK2 activated?

A

CDK4/6 sequestering p21 and p27

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20
Q

Function of active cyclin E-CDK2:

A

It phosphorylates p27 which marks it for degradation by the proteasome, allowing for more active cyclin E-CDK2 complexes to be generated and leading to hyperphosphorylation of RB.

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21
Q

What happens when RB is hyperphosphorylated

A

Hyperphosphorylation makes RB inactive which allows for the release of E2F and HDAC which are needed for S phase gene expression.

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22
Q

Nuclear RB protein is a member of?

A

The “pocket proteins”

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23
Q

What is HDAC

A

It is an enzyme (histone deacetylase) that when bound to RB it blocks S phase gene expression.

24
Q

What is E2F

A

-E2F is a key transcriptional regulator of S-phase genes
-Positive regulator of cell cycle progression
-Active E2Fs1,2,3 induce expression of late G1 genes, required for S phase.

25
Q

How is E2F1 degraded

A

In the G1/S transition cyclin A and CDK2 phosphorylates both E2F and DP subunits; leading to their dissociation, and loss of transcriptional activities.

26
Q

What are E2Fs1,2 and 3a

A

They are Hsp (heat shock protein)-chaperones also know as ‘activating E2Fs’

27
Q

S-Phase gene expression leads to:

A

-DNA polymerase, topoisomerase, ligase etc
-Initiation Factors
-Structural proteins (e.g. Histones)
-Proteins involved in synthesizing DNA precursor nucleotides
-Spindle assembly checkpoint protein e.g MAD2

28
Q

What cyclin is involved in G2/M Phase Progression

A

Cyclin B partnered with CDK1

29
Q

What keeps CDK1 inactive

A

The kinases WEE1 and MYT1

30
Q

What activates CDK1

A

Two independent events:
1. CAK-mediated phosphorylation
2. Cdc25-mediated dephosphorylation

31
Q

Targets of Active CDK1/Cyclin B:

A

– phosphorylates serine residues on lamin (breakdown of nuclear membrane)
– Phosphorylates histones
– Phosphorylates microtubule associated proteins (altered behavior during mitosis)

32
Q

What are CDC25 Phosphatases

A

-They are a family of phosphatases (A, B, C) that dephosphorylate specific tyrosine and
threonine residues on CDKs (which inhibit CDK function)
-Also dephosphorylates inhibitory phosphorylation residues on CDK2 in G1

33
Q

Which cell cycle stages are CDC25s involved in

A

G1-S and G2-M transitions.

34
Q

Why are CDC25 phosphatases targets of the checkpoint machinery during DNA damage

A

Because they allow for progression through the cell cycle, so in order to prevent this they are inactivated or degraded.

35
Q

Overexpression of CDC25A and B is seen in?

A

High grade tumors and poor prognosis cancers.

36
Q

What are checkpoint kinases (CHK)

A

They are kinases activated in response to DNA damage and target CDC25.

37
Q

What is Spindle Assembly Checkpoint

A

It ensures proper segregation of sister chromatids by inhibiting metaphase to anaphase transition until all chromosomes are attached correctly to the mitotic spindle.

38
Q

What are Cohesins?

A

Protein complexes that hold together sister chromatids.

39
Q

What is separase?

A

It is a protease which cleaves cohesins

40
Q

What happens when chromosomes are unaligned?

A

Separase is kept inactive by securin and Cdk1-cyclinB

41
Q

What happens when chromosomes become aligned?

A

CyclinB and securin are ubiquitinylated by the Anaphase Promoting Complex (APC)-CDC20 complex and degraded. This leads to the activation of separase, which releases sister chromatids, allowing for metaphase to anaphase transition.

42
Q

MYC represses expression of what?

A

p15 and p21

43
Q

TGFb reduces what expression?

A
  1. c-MYC expression-Smad3 and E2F4/5
  2. p107 shut down c-MYC expression
44
Q

TGFb-mediated repression of MYC is lost in what cancer?

A

Breast cancer

45
Q

How does TGFB induce expression of p21 and p15?

A

TGFb signalling: Smad2/3 associate with Smad4 heterotrimeric complex moves to nucleus and collaborates with the transcription factor Miz-1 to induce expression

46
Q

P21 and P15 are repressed in what cancers?

A

Any cancers where MYC is overexpressed

47
Q

How does TGFb block cell cycle progression.

A

By preventing phosphorylation of RB, which prevents it from releasing E2F.

48
Q

What is Akt

A

It is a serine/threonine kinase which is activated downstream of growth factor receptors. Its function is to promote cell cycle progression.

49
Q

3 functions of Akt:

A

-Inhibition of CDK Inhibitors (p21 and p27).
-Promotes cell cycle progression by blocking the actions of GSK3b.
-Blocks the actions of a pro-apoptotic protein Bad.

50
Q

How does Akt inhibit CDKIs p21 and p27?

A

Akt phosphorylates them which leads to their translocation from the nucleus to the cytoplasm where they are degraded by the proteosome

51
Q

Targets of GSK3b

A

It has inhibitory actions on MYC and CyclinD1.

52
Q

What does Autonomous cell division mean?

A

The cell no longer depends on positive and negative growth factors (i.e cells are now cancerous).

53
Q

What pathways play a central role in transmitting oncogenic signals.

A

-The PI3K-AKT pathway
-The RAS-RAF-MEK-ERK pathways

54
Q

Increased Akt activity is frequent in what cancers?

A

Breast cancer.

55
Q

Tumor grade can be linked with?

A

Higher pAKT expression and reduced nuclear P27.

Tumour (8 decks)

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