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Molecular Basis of Disease > Mechanism Of Disease 1: Cell Growth and Cell Differentiation > Flashcards

Mechanism Of Disease 1: Cell Growth and Cell Differentiation Flashcards

1
Q

What is cell growth and cell differentiation? (which comes first)

A

Cell growth = multipotent cells (stem cells) divide to produce more cells
Differentiation = cells become specialised + more complex (lose potency) ending growth

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2
Q

How can cell grwoth + differentiation lead to disease?

A

Developmental conditions (e.g. neural tube defects - spina bifida)
Neoplasia (+ metaplasia) - cancer and tumours
Cell growth related e.g. cardiac hypertrophy

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3
Q

What is metaplasia?

A

Replacement of one differentiated somatic cell type to another in same tissue (uncontrolled during reproduction = metaplasia, otherwise normally required)

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4
Q

What is a somatic cell?

A

Any cell apart from a gamete, germ cells and undifferentiated stem cells.

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5
Q

What are the 2 types of cell growth?

A

Hypertrophy - bigger cells

Hyperplasia - more cells - more common

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6
Q

What causes hypertrophy? + example

A

Cells grow bigger due to elevated protein synthesis so more proteins, lipid and nucleotides produced.
Example - heart (cardiac hypertrophy)

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7
Q

What causes hyperplasia?

A

Increased cell division/proliferation due to cell cycle - more cells produced

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8
Q

What are the steps in cell differentiation?

A
  • Cell exits cell cycle becoming “post-mitotic”
  • Cell type specific expression
  • Specific gene expression causes cell morphology and function changes
    (terminally differentiated and can’t return to cell cycle)
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9
Q

Which mechanism controls cell growth and differentiation?

A

Intra and extracellular signals e.g. checks on cells, growth and inhibitory factors, cell adhesion

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10
Q

What do intra/extracellular signals interact to cause cell growth/differentiation?

A

On promoters as co-incidence detectors. (multiple factors required to decide if gene will be expressed or not)

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11
Q

Wha are the steps for extracellular signals?

A

Ligand (e.g. a growth factor) binds to receptor causing intracellular cascade (e.g. kinase cascade)
Cascade causes transcription factor activation in nucleus + downstream genes are expressed.
mRNA produced and proteinsynthesis occurs (translation).
Proteins produced go onto directly affect the cell or cause more transcription factors to affect downstream genes.

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12
Q

What are the 3 types of extracellular signals?

A

Paracrine
Autocrine
Endocrine

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13
Q

What are paracrine extracellular signals?

A

Cell non-autonomous example
Ligands produced locally (near cell) to stimulate proliferation of a different cell type with correct cell surface receptor

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14
Q

What are autocrine extracellular signals?

A

Cell autonomous example

Ligand produced by own cell and affects itself by attaching to own appropriate receptors (produces own cascade)

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15
Q

What are endocrine extracellular signals?

A

Like hormones. Released systemically (into general circulation) for distant effects

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16
Q

What are the 4 different effects of the extracellular signalling proteins? + example proteins for each

A
  • Stimulate proliferation via mitogens (e.g. EGF, IL2)
  • Induce differentiation + inhibit proliferation (e.g. TGFbeta)
  • Can do either cell proliferation or differentiation (e.g. Wnt ligands)
  • Induce apoptosis (e.g. TNF family e.g. TNFa)
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17
Q

What are mitogens? + examples

A

Protein that induces cell division e.g Growth factors and interleukins such as EGF, FGF, NGF, IGF1, IL2, IL4)

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18
Q

What are the phases of the cell cycle?

A 
G1 phase (growth)
S phases (synthesis of DNA) - DNA replication
G2 phase (growth)
M phase (mitosis)
G0 phase - quiescent cells (left cell cycle)
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19
Q

What happens to quiescent cells? - entire journey

A

Cells in G0 phase either rejoin cell cycle or undergo terminal differentiation (post-mitotic cell) which after it’s lifespan undergoes apoptosis (cell shedding)

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20
Q

Which part of cell cycle is ploidy 2N?

A

Diploid in G1 phase before DNA replication in S phase

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21
Q

Which part of cell cycle is ploidy 4N?

A

Tetraploid in G2 phase after DNA replication in S phase

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22
Q

What stages are in interphase?

A

G1, S and G2

23
Q

How do we look at cells in the cell cycle? + determine which stage they’re in (2 methods)

A
  • DNA stain applied and FACs measure DNA content of every cell in a. population
  • Fluroscence microscopy
24
Q

How would FAC analysis graph look if rate of division was low and why?

A

G1 would be vert high showing cells aren’t too proliferative. S would be lowest and G2/M slightly higher

25
Q

How would FAC analysis graph look if rate of division was high and why?

A

G1 is much lower wherease S is much higher. G2/M stays the same because it’s a time limited part of cycle.

26
Q

What does fluorescence microscopy show? - look at pictures in detail

A

Shows interphase as 1 phase and all phases of mitosis by showing presence of tubulin, CHEK 2 (mitotic protein) co-localised and centrioles.

27
Q

What are the phase of mitosis and what happens in each phase?

A 
Prophase
- nucleus less definite 
- microtubular spindle assemble and centrioles migrate to poles
Prometaphase
- nuclear membrane breaks down
- Kinetochores attach to spindle 
Metaphase
- Chromosomes align in equatorial plane
Anaphase
- Chromatids separate and migrate to opposite poles
elophase
- Daughter nuclei form
Cytokinesis
- Division of cytoplas
- Chromosomes decondense
28
Q

What are the 3 cell cycle checkpoints?

A

1 - restriction point (most important) - checks if DNA not damaged, cell size and metabolite stores
2 - G2/M phase checkpoint - checks if DNA completely replicated and DNA not damaged
3 - M phase checkpoint - checks if chromosomes are aligned on spindle so there will be the right number of chromosomes in each daughter cell

29
Q

Why are there cell cycle checkpoints?

A

Makes sure synthesis (S phase) and mitosis (M phase) is separated so mitosis only occurs when DNA is completely synthesised and vice versa.

30
Q

Why is the restriction point the most important cell cycle checkpoint?

A

Cell are responsive to growth factors (extracellular signals) in G1 phase before restriction point. This allows cell growth and the point determines if G0 cells have re-entered cell cycle.

31
Q

What controls the cell cycle?

A

Controls such as protein kinases and phosphatases to ensure strict alternation of mitosis and DNA replication.

32
Q

What do protein kinases and phosphotases do?

A

Protein kinases attach phosphate groups.

Phosphotases remove phosphate groups (dephosphorylate)

33
Q

What are CDKs?

A

Cyclin dependent kinase - type of protein kinase catalysing phosphorylation of specific substrates

34
Q

What are cyclins?

A

Regulatory subunit that must bind to CDK for it to function.

35
Q

What are the steps of active cyclin-CDK complex forming?

A

Expression of cyclin due to extracellular signals (growth factors). When there is enough it binds to CDK forming the active cyclin-CDK complex which can now go onto phosphorylate specific substrates.

36
Q

What 4 ways is Cyclin-CDK activity self-regulated?

A
  • Cycle of synthesis (of cyclin via gene expression) and destruction of cyclins (by proteosomes)
  • Post-translational modifications phosphorylate cyclins (can cause activation, inhibition, or destruction - increase target for proteosome)
  • Dephosphorylation
  • Binding of cyclin-dependent kinase inhibitors (CDKIs)
37
Q

What is retinoblastoma protein (RB)?

A

RB is a key substrate of G1 and G1/S cyclin dependent kinases (CDKs).
It is a tumour suppressor preventing cell cycle entry by keeping E2F bound to it.

38
Q

What are the steps for CDK and Retinoblastoma protein causing DNA replication?

A

In normal conditions unphosphorylated RB protein is bound to E2F which prevents stimulation of S phase protein expression.

Cyclin D-CDK4 and Cyclin E-CDK2 phosphorylates RB releasing E2F.

E2F now stimulates cyclin E expression (+ve feedback) and S phase protein allowing DNA replication to begin.

39
Q

What is E2F?

A

It is a transcription factors that normally binds to a promoter driving transcription and allowing S phase protein expression.

40
Q

Give examples of S phase proteins?

A

DNA polymerase, thymidine kinase, PCNA

41
Q

What are the steps in the entire cycle for RB proteins causing mitosis (entry into cycle)? - long

A

1) Mitogens triggers entire process in G1 phase by signalling to nucleus + induces transcription of early genes
2) Early gene make transcription factors that drive delayed gene transcription.
3) Delayed gene transcription makes cyclin D.
4) Cyclin D-CDK4/6 active complex forms and hypophosphorylates (some E2F activity)
5) E2F activity increases cyclin E forming cyclin E-CDK2 active complex.
6) This complex hyperphophorylates RB - loses ability to suppress E2F
7) E2F +ve feecbacks for cyclin E and activates E2F responsive genes required for S phase due to hyperphosphorylation of RB
8) Cyclins continuously activate more in a cycle

End of mitosis only when RB dephosphorylated by PP1 (phosphotase)

42
Q

When do S phase cyclin-CDKs and G2/M phase cyclin-CDKs cause cell to go through S phase and mitosis?

A

They are initially in inactive forms but switched activated by post-translational modifications and inhibitors removed allowing cell to progress through S phase and mitosis.

43
Q

What 3 steps occur during the cell cycle if DNA damage detected at a checkpoint?

A

1) Stop the cell cycle (using CDKIs and CHEK2) - CDKI genes expressed
2) Attempt DNA repair e,g mismatch repair
3) Too much damage and repair impossible = programmed cell death (apoptosis) by BCL2 family and capsases which are involved in apoptosis (genes activated to produce them)

44
Q

What is TP53?

A

Tumour protein p53 involved in cell cycle and apoptosis (tumour suppressor gene, similair to Rb gene)

45
Q

Steps of TP53 activation

A

1) Mutagen damages DNA
2) Damage causes kinase activation leading to Tp53 phosphorylation (Tp53 now activated and can’t be destroyed by proteosome)

46
Q

What are the 3 biological effects of Tp53?

A

1) Drives transcription for expression of CDK1 - so cell cycle arrests
2) DNA repair e.g excision repair
3) If repair not possible and cell can’t return to cell cycle, Tp53 causes apoptosis

47
Q

What are Tp53 levels when DNA is not damaged?

A

Tp53 low as it is continuously destroyed by proteosomes until it’s phosphorylated due to kinase activation

48
Q

How does Tp53 lead to cancer?

A

Loss of TP53 funcition mutations

  • prevents cells cycle arrest after DNA damage so faster growth
  • prevent apoptosis - damaged cells don’t die
  • prevent DNA repair - more mutations = cancer progression
49
Q

How does chemotherapeutic drugs work?

A

The drugs act on the cell cycle to stop proliferation and induce apoptsosis.

50
Q

What do S phase chemotherapeutic drugs do + 2 drug examples?

A

S phase drugs cause DNA damage

5-fluorouracil (prevent thymidine synthesis)
Cisplatin (binds to DNA causing damage and blocks repair)

51
Q

What do M phase chemotherapeutic drugs do + 2 drug examples?

A

M phase drugs target mitotic spindle

Vinca alkaloids - bind to free monomeric tubulin and stabilise them. Prevent microtubule polymerisation so mitotic spindle can’t form and cells arrest in mitosis

Paclitaxel (taxol) - bind to polymerised tubules and stablise microtubules to prevent de-polymerisation arresting cells in mitosis

52
Q

What is colchicine? + what does it do

A

A M phase drug (same mechanism of vinca alklaloids)

- used as immunosuppressant

53
Q

Explain which cyclin-CDKs are activated when?

A

When growth factors binds to receptor and induce gene expression, cyclins are made.

G1 and G1/S cyclin CDKs phosphorylate substrate when CDKI not present
S phase cyclin CDKs cause DNA replication (gene expression of S phase proteins)
G2/M cyclin CDKs cause cells to enter mitosis if all DNA is replicated as chromosomes align on spindle

Failure = TP53 cause apoptosis

54
Q

What regulates CDKIs?

A

TP53 and TGF beta

Molecular Basis of Disease (29 decks)

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