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MBD > Mechanisms of Disease 1 - Cell Growth and Cell Differentiation > Flashcards

Mechanisms of Disease 1 - Cell Growth and Cell Differentiation Flashcards

1
Q

What is cell growth and differentiation and what are they repsonsible for?

A
  • Cell growth – a bigger organism more cells
  • Differentiation – cells become complex (usually) an end to growth.
  • Cell growth precedes differentiation, but with some overlap.

They are the basic mechanisms responsible for turning a zygote into a mature multicellular organism.

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2
Q

What 3 groups do diseases related to cell growth and differentiation fall into?

A
  • Developmental conditions
  • Neoplasia (and metaplasia)
  • Others
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3
Q

What are developmental conditions and what is example?

A
  • Can be related to cell growth or differentiation (or both)
  • E.g neural tube defects like spina bifida
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4
Q

What are some examples of neoplasia (and metaplasia)

A

E.g Cancer, tumours

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5
Q

What is an example of another disorder related with growth/ differentiation?

A

e.g cardiac hypertrophy

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6
Q

What are the 2 main forms of cell growth and what are they balanced by?

A
  • Hypertrophy (bigger cells)
  • Hyperplasia (more cells)
  • Cell growth is balanced by cell death
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7
Q

What is hypertrophy?

A
  • Hypertrophy is simply cells growing bigger
    • more proteins, more membranes
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8
Q

What drives hypertrophy?

A
  • Elevated protein synthesis is a big driver for increased cell size.
    • E.g the heart
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9
Q

What is Hyperplasia?

A
  • More cells is caused by cell division or proliferation
    • Cell cycle
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10
Q

What is differentiation?

A
  • Beginning of exit of cells from the cell cycle – Differentiated cells are ‘post-mitotic’
  • A program of cell type-specific gene expression
  • Cell morphology and function changes.
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11
Q

What are the similarities between growth and differentiation?

A
  • The mechanisms governing them
  • Cell growth and differentiation are governed by the integration of multiple signals
    • Intra- and extracellular signals (checks on cellular physiology, growth and inhibitory factors, cell adhesion etc)
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12
Q

How do these signals involved in differentiation/ cell growth work?

A
  • Signals converge on the promoters of key genes.
    • Promoters act as “co-incidence detectors” – promoters converge the signals
    • Right combination of signals received by promoter, it will make a binary decision on if the gene is expressed YES/NO? but also how much is made.
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13
Q

What are extracellular signals?

A
  • Ligand binds to receptor to cause intracellular cascade which activates transcription factors in the nucleus which drive gene expression creating mRNA
  • the mRNA is exported back to the cytoplasm for protein transcription and translation.
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14
Q

What are the 3 broad classes of extracellular signals?

A
  • Paracrine
  • Autocrine
  • Endocrine
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15
Q

What are paracrine signals?

A

Produced locally to stimulate proliferation of a different cell type that has the appropriate cell surface receptor.

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16
Q

What are autocrine signals?

A

Produced by a cell that also expresses the appropriate cell surface receptor. Cell-autonomous

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17
Q

What are endocrine signals?

A

Conventional hormones, released systemically for distant effects.

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18
Q

What are the extracellular signals in cell growth and differentiation?

A

Proteins that:

  • Stimulate proliferation and promote survival
    • Mitogens e.g growth factors and interleukins (EGF, FGF, NGF, PDGF, IGF1, IL2, IL4)
  • Induce differentiation and inhibit proliferation e.g TGFb
  • Can do either e.g Wnt ligands
  • Induce apoptosis e.g TNFa and other members of the TNF family.
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19
Q

What are the phases of the cell cycle?

A

Mitosis, G1, S phase, G2

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20
Q

What are quiescent cells and what phase are they in?

A

Cells that have left the cell cycle- G0

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21
Q

Can quiescent cells rejoin the cell cycle?

A

Yes

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22
Q

How many chromosomes are there after mitosis?

A

After mitosis, the cell is diploid with 2n (G0 and G1 cells).

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23
Q

How many chromosomes are there going into mitosis (G2/M)

A

After genome replication there is a 4n genome going into mitosis (G2/M)

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24
Q

How many chromosomes are there during S phase of the cell cycle

A

The number of chromosomes during S phase is inbetween the amount before end of mitosis and after genome replication (between 2n and 4n)

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25
Q

What is the FACS analysis of cell DNA content?

A
  • Flow cytometry
  • If a DNA stain is applied, FACs can measure the DNA content of every cell in a population
    • Strength of staining correlates with the amount of DNA in the cell of a population.
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26
Q

Why does G2 stay the same here?

A

It is a time limited part of the cell cycle.

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27
Q

What ways can you look at the cell cycle?

A
  • Fluorescence microscopy
  • Flow Cytometry
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28
Q

What are the steps of mitosis?

A
  • Prophase (1)
  • Prometaphase
  • Metaphase (2)
  • Anaphase (3)
  • Telophase (4)
  • Cytokinesis
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29
Q

What happens in prophase?

A
  • Nucleus becomes less definite
  • Microtubular spindle apparatus assembles
  • Centrioles migrate to poles.
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30
Q

What happens in prometaphase?

A
  • Nuclear membrane breaks down
  • Kinetochores attach to spindle in nuclear region
31
Q

What happens in metaphase?

A

Chromosomes align in equatorial plane

32
Q

What happens in Anaphase?

A

Chromatids separate and migrate to opposite poles

33
Q

What happens in Telophase?

A

Daughter nuclei form

34
Q

What happens in Cytokinesis?

A
  • Division of cytoplasm
  • Chromosomes decondense
35
Q

What are cell cycle checkpoints?

A

These are the controls (involve specific protein kinases and phosphatases) ensure the strict alternation of mitosis and DNA replication.

36
Q

List the cell cycle checkpoints.

A
  1. Restriction point
  2. G2/M phase checkpoint
  3. Mitosis
37
Q

What is the restriction check point?

A
  1. Restriction point – checks DNA is not damaged, cell size (large enough to divide into 2), metabolite/nutrient stores (enough energy to complete mitosis)
38
Q

What is the G2/M phase checkpoint?

A
  1. G2/M phase checkpoint – checks if DNA is damaged, and the DNA is completely replicated.
39
Q

What is the Mitosis checkpoint?

A

Mitosis – checks chromosomes are aligned correctly on the spindle to ensure right number of chromosomes go into daughter cells.

40
Q

Where do external signals act?

A
  • In the G1 phase up until the restriction point.
  • External signals act on G0 cells as this is the main site of control for cell growth.
41
Q

In humans how many genes code for CDKs and Cyclin?

A
  • In humans there are 10 genes encoding CDKs and >20 genes encoding Cyclin.
  • Expression of cyclins that is controlled by mitotic signals from growth factors.
42
Q

What does CDK stand for?

A

Cyclin dependent kinases

43
Q

What does cyclin do?

A

It is a regulatory subunit

44
Q

What is cyclin expression induced by?

A

Growth factors

45
Q

What is the role of Cyclin-dependent Kinases (CDK)?

A

It is a catalytic subunit

46
Q

What is active Cyclin- CDK complex?

A

Cyclin forms a complex with CDK resulting in → active Cyclin-CDK complex which phosphorylates specific substrates.

47
Q

What destroys the cyclin-CDK complex?

A

Prorteasomes

48
Q

What does post-translational phosphorylation result in?

A

Activation, inhibition or destruction

49
Q

How is Cycin-CDK activity regulated?

A
  • Cyclin proteins have a high rate of turnover: continually synthesised (gene expression) then destroyed (by proteasome).
  • Post translational modification by phosphorylation may result in activation, inhibition or destruction.
  • Dephosphorylation
  • Binding of cyclin-dependent kinase inhibitors (CDKIs)
50
Q

What is the retinoblastoma protein (RB)?

A
  • RB is a key substrate of G1 and G1/S cyclin-dependent kinases.
51
Q

What does E2F usually do?

A

E2F drives the production of S phase proteins.

52
Q

How do E2F and RB work together in the cell cycle?

A
  • When unphosphorylated RB binds to E2F transcription factor it prevents the stimulation of S-Phase protein expression
  • The unphosphorylated RB bound to E2F interacts with Cyclin D-CDK4 & Cyclin E-CDK2 then RB becomes phosphorylated and dissociated from E2F.
  • Thus E2F is no longer repressed and can bind to promoters of its target genes, allowing replication to start.
  • E2F binds to promoter of cyclin E which when it becomes partially active it creates a positive feed forward loop.
    • More Cyclin E and s-phase proteins created so DNA replication starts.
53
Q

What are some cyclin E and S phase promoters?

A

DNA polymerase, thymidine kinase, PCNA

54
Q

What are the sequence of events triggered by growth factors?

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.
  • E2F sequestered by binding to unphosphorylated retinoblastoma protein (RB).
  • G1 cyclin-CDK complexes hypophosphorylate RB and then G1/S cyclin-CDK complexes hyperphosphorylate RB releasing E2F
  • E2F stimulates expression of more Cyclin E and S-phase proteins (e.g DNA polymerase, thymidine kinase, proliferating cell nuclear antigen etc)
  • S-phase cyclin-CDK and G2/M cyclin-CDK complexes build up in inactive forms. These switches are activated by post-translational modification or removal of inhibitors driving the cell through S-phase and mitosis.
55
Q

After DNA damage is detected at checkpoints, what does this lead to?

A
  • Stopping the cycle (e.g CDKIs, CHEK2 etc)
  • Attempt DNA repair (nucleotide or base excision enzymes, mismatch repair etc)
  • If repair impossible, programmed cell death (BCL2 family, caspases)
56
Q

What is stopping of the cell cycle driven by?

A

CDKI genes

57
Q

What things attempt DNA repair?

A

Nucleotide or base excision enzymes, mismatch repair etc

58
Q

What causes programmed cell death?

A

BCL2 family or caspases

59
Q

What is the role of TP53?

A
  • Tumour protein 53 – P53 means protein of 53 kDa.
  • TP53 is a tumour suppressor gene.
    *
60
Q

What happens to TP53 if DNA is intact?

A
  • If DNA is intact, TP53 is destroyed continually by the proteasome
61
Q

What happens to TP53 if DNA is damaged?

A
  • If DNA is damaged, important protein kinases are activated which phosphorylate TP53
  • TP53 now can no longer be destroyed by proteasome.
    • TP53 accumulates and exerts biological effects to that cell.
62
Q

What are the functions of phosphorylated TP53?

A
  • Expression of CKI – Cell cycle arrest
  • Activation of DNA repair e.g excision repair
  • If repair not possible, P53 activates apoptosis
63
Q

What mutations are the most frequent in cancer?

A

TP53 loss of function

64
Q

How does TP53 loss of function causes cancer link?

A
  • Prevent cell cycle arrest – faster growth
  • Prevent apoptosis – cells do not die
  • Prevent DNA repair – more mutations lead to more heterogeneity, more adaptation to environment and cancer progression as a result.
65
Q

What is the aim of chemotherapeutic drugs?

A

To act on the cell cycle – objective is to stop proliferation and induce apoptosis.

66
Q

What are the 2 S-phase chemotherapeutic drugs and what do they cause?

A
  • 5-fluorouracil
  • Cisplatin
67
Q

What do the 2 S-phase chemotherapeutic drugs cause?

A

DNA damage

68
Q

How does cistplain work?

A

binds to DNa causing damage and blocking repair

69
Q

How does 5-fluorouracil work?

A

Prevents synthesis of thymidine

70
Q

What do the M-phase chemotherapeutic drugs do?

A

Target the mitotic spindle.

71
Q

What are the 2 M-Phase chemo drugs

A
  • Vinca alkaloids
  • Paclitaxel (Taxol)
72
Q

What does paclitaxel do?

A
  • Stabilises microtubules
  • Preventing de-polymerisation
  • Arrests cells in mitosis
73
Q

What do vinca alkaloids do?

A
  • Stabilise free tubulin
  • Prevents microtubule polymerization
  • Results in arrest of cells in mitosis
74
Q

What is colchicine used for?

A

Not just cancer, similar mode of action to vinca alkaloids and is used for immune-suppression.

MBD (23 decks)

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