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Molecular basis of disease > Cell growth and differentiation > Flashcards

Cell growth and differentiation Flashcards

1
Q

What are growth factors, cytokines and interleukins?

What are their functions?

A

Proteins which:

  • stimulate proliferation (called mitogens) and maintain survival
  • stimulate differentiation and inhibit proliferation (e.g. TGFβ)
  • induce apoptosis (e.g. TNF⍺ and other members of the TNF family)
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2
Q

Where are growth factors, cytokines and interleukins derived from?

A

From 3 different sources:

  • Paracrine: produced locally to stimulate proliferation of a different (nearby) cell type with the appropriate cell surface receptor
  • Autocrine: produced by a cell that also expresses the appropriate cell surface receptor
  • Endocrine: like conventional hormones, released systemically for distant effects
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3
Q

Phases of the cell cycle

A

Mitotic (M) phase

Interphase (G1,S,G2)

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4
Q

What happens in the M phase of the cell cycle?

A
  • Separation of chromosomes into two sets

- Cell divides its cytoplasm, forming two new cells

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5
Q

What happens during interphase?

A

G1:
-cells grow physically larger and copies organelles

S phase:
-cell synthesises a complete copy of DNA in its nucleus and duplicates the centrosome, which helps separate the DNA during M phase

G2 phase:
-cell grows more, makes proteins and organelles, and begins to reorganise its contents in preparation for mitosis

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6
Q

What is the G0 phase?

A

After cell division, some cells may exit the G1 phase and enter a resting state (G0 phase). Here, cells are not actively preparing to divide and are considered quiescent.

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7
Q

What is the fate of G0 cells?

A
  • Re-enter G1 phase in presence of mitogens

- Terminal differentiation (post-mitotic cells) which eventually undergo cell shedding & apoptosis

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8
Q

How is the rate of cell division measured?

A

Fluorescence-activated cell sorting (FACS) is used to determine the rate of cell division and the phase of the cell cycle at which cells are at.

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9
Q

Fluorescence activated cell sorting: Steps

A

1) Cells are obtained
2) DNA is labelled with fluorescent dye
3) Fluorescent dye is read by a laser
4) Laser provides information about DNA content by analysing how fluorescent the nuclei are

The DNA content is greater is G2/M phase because of the replication at S phase

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10
Q

Stages of mitosis

A

Four main stages:

1) Prophase/Prometaphase
2) Metaphase
3) Anaphase
4) Telophase

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11
Q

Prophase

A
  • nucleus becomes less definite
  • microtubular spindle apparatus assembles
  • centrioles migrate to poles
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12
Q

Prometaphase

A
  • nuclear envelope breaks down

- kinetochores attach to spindle via microtubules

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13
Q

Metaphase

A

chromosomes align in equatorial plane

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14
Q

Anaphase

A

chromatids separate and migrate to opposite poles

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15
Q

Telophase

A

daughter nuclei form

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16
Q

What is after mitosis?

A

cytokinesis

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17
Q

Cytokinesis

A
  • division of the cytoplasm to form two separate daughter cells
  • chromosomes decondense
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18
Q

5-Fluorouracil

A

S-Phase Active Drug:
-thymidine analogue which blocks thymidylate synthesis, preventing thymidine production and therefore preventing DNA replication

*used in cancer treatment

19
Q

Bromodeoxyuridine (BrdU)

A

S-Phase Active Drug:
-thymidine analogue that is incorporated into DNA and detected by antibodies to identify proliferating cells that have passed through the S-phase

20
Q

Colchicine

A

M-Phase Active Drug:

  • stabilises free tubulin, preventing microtubule polymerisation and arresting cells in mitosis
  • used in karyotype analysis
21
Q

Vinca alkaloids

A

M-Phase Active Drug:
-like colchicine, stabilises free tubulin, preventing microtubule polymerisation and arresting cells in mitosis

*used in cancer treatment

22
Q

Paclitaxel (Taxol)

A

M-Phase Active Drug:
-stabilises microtubules, preventing de-polymerisation and cells will be arrested in the M-phase

*used in cancer treatment

23
Q

Cell cycle checkpoints

A

There are controls (involving specific protein kinases and phosphatases) that ensure the strict alternation of mitosis and DNA replication
G1,G2,M checkpoint
*learn diagram

24
Q

What controls cell cycle progression?

A

Cyclin-dependent kinase activity

25
Q

Cell cycle regulators

A

· Cyclin Dependant Kinases (CDKs)- enzymes that phosphorylate the target proteins. They become active when bound to a corresponding cyclin.

· Cyclins- regulators of CDKs. Different cyclins are produced at each phase of the cell cycle.

26
Q

Regulation of Cyclin-CDK Activity

A

· Cyclin synthesis (gene expression) and destruction (by proteasome)
· Post-translational modification by phosphorylation- depending on the modification site may result in activation, inhibition or destruction
· Dephosphorylation
· Binding of cyclin-dependent kinase inhibitors

27
Q

The function of retinoblastoma protein in cell cycle

A

pRB is unphosphorylated and binds E2F transcription factor preventing its stimulation of S-phase protein expression
>inhibits S-phase

28
Q

What affects the binding of pRB to E2F?

A

In presence of Cyclin D-CDK4 complex or Cyclin E-CDK2 complex, retinoblastoma protein becomes phosphorylated,

it is no longer able to bind E2F. E2F is therefore released and stimulates the expression of more Cyclin E and S-phase proteins e.g. DNA polymerase, thymidine kinase, Proliferating Cell Nuclear Antigen etc.
>DNA replication then starts.

29
Q

Cyclin Dependent Kinase Inhibitors (CKIs)

A

Two families:

CDK Inhibitory Protein/Kinase Inhibitor Protein (CIP/KIP) Family
>now called CDKN1

Inhibitor of Kinase 4 Family (INK4)
>now called CDKN2

30
Q

CDK Inhibitory Protein/Kinase Inhibitor Protein (CIP/KIP) Family

A
  • Expression of members of this family stimulated weakly by TGFβ and strongly by DNA damage (involving TP53)
  • Inhibit all other CDK-cyclin complexes (late G1, G2 and M)
  • Are gradually sequestered by G1 CDKs thus allowing activation of later CDKs
31
Q

Inhibitor of Kinase 4 Family (INK4)

A
  • Expression stimulated by TGFβ

- Specifically inhibit G1 CDKs (e.g. CDK4 the kinase activated by growth factors)

32
Q

What induces cyclin expression?

A

Growth factors (mitogens)

33
Q

How do growth factors (mitogens) induce cyclin expression?

A

1) Growth factor binds growth factor receptor on cell membrane
2) Signal transducers are activated- which are a cascade of different components which eventually affect waves of transcription factor activation/expression in the nucleus
3) mRNA produced which then codes for a protein with specific effects

34
Q

Effect of growth factor signalling on gene expression

A

Growth factor signalling activates early gene expression (transcription factors- FOS, JUN, MYC).

Early gene products stimulate delayed gene expression (includes Cyclin D, CDK2/4 and E2F transcription factors).

35
Q

What hypophosphorylates pRB?

A

G1 cyclin-CDK complexes hypophosphorylate pRB

36
Q

What hyperphosphorylates pRb?

A

G1/S cyclin-CDK complexes hyperphosphorylate pRB releasing E2F

37
Q

How is hyperphosphorylated pRB dephosphorylated?

A

by protein phosphatase 1

38
Q

Which cyclin-CDK complexes build up in inactive forms?

A

S phase and G2/M phase cyclin-CDK complexes
-switches are activated by post-translational modification or removal of inhibitors, driving the cell through S-phase and mitosis

39
Q

Which CDKs are activated in response to environmental signals?

A

G1 CDKs

40
Q

Function of different CDKs

A

G1 CDKs hypophosphorylate

Late CDKs hyperphosphorylate

41
Q

Effect of DNA damage in cell cycle

A

DNA damage detected at checkpoints triggers cell cycle arrest or apoptosis

42
Q

Essential transcription factor in response to DNA damage is…

A

TP53

43
Q

TP53 in response to DNA damage

A

1) Mutagen causes DNA damage which activates kinases, and in turn activates CHEK2
2) This causes phosphorylation of TP53
3) TP53 phosphorylation allows it to survive and it is no longer quickly degraded, becoming a stable protein
4) TP53 is now active and binds promoters of transcription factors to express genes required for DNA repair
5) If DNA cannot be repaired, TP53 triggers apoptosis
6) TP53 also expresses CKIs to induce cell cycle arrest

Molecular basis of disease (31 decks)

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