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molecular basis of disease > Mechanisms of disease I > Flashcards

Mechanisms of disease I Flashcards

1
Q

Define cell growth and cell differentiation.

A

-process responsible for turning zygote into a mature multicellular organism.

=>cell growth = a bigger organism, more cells
=>cell differentiation = cells become complex, puts an end to cell growth.

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2
Q

What are the 3 main categories of disease related to cell growth and differentiation?

A
  1. developmental conditions => eg. neural tube defects like spina bifida
  2. neoplasia = cancer, tumour
  3. others = eg. cardiac hypertrophy
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3
Q

What are two main forms of cell growth?

A
  1. hypertrophy (bigger cells due to elevated protein synthesis)
  2. hyperplasia (cell division an proliferation)-> more common in human.
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4
Q

Define differentiation

A

exit from the cell cycle 1. differentiated cells are “post -mitotic”

  1. a program of cell type-specific gene expression
  2. cell morphology and function changes
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5
Q

what are similarities between cell growth and differentiation?

A

1) mechanisms governing them : intra and extracellular signals(checks on cellular physiology, growth and inhibitory factors, cell adhesion)
2) signals converge on the promoters of key genes ( promoters act as ‘co-incidence detectors’)

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6
Q

what are 3 broad classes of extra cellular signals?

A
  1. paracrine =produced locally to stimulate proliferation of a different cell type that has the appropriate cell surface receptor.
  2. autocrine = produced by a cell that also expresses the appropriate cell surface receptor.
  3. endocrine = like conventional hormones, release systemically for distant effects.
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7
Q

What is the function of extracellular signals in cell growth and differentiation?

A

lead to production of proteins that:
->stimulate proliferation and promote survival eg. mitogens
(growth factors)
-> induce differentiation and inhibit proliferation , eg. TGF beta, Wnt ligands
-> apoptosis

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8
Q

How can phases of cell cycle be identified?

A
  • by looking at ploidy (number of sets of chromosomes in a cell, ie diploid, tetraploid)
  • G1 = 2N, diploid
  • S = mix of 2N and 4N
  • G2/mitosis = 4N , tetraploid
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9
Q

What technique is used to measure proliferation of cells?

A

FACS => fluorescence activated cell sorting,
if DNA stain is applied then FACs can measure the DNA content of every cel in a population.
1. high proliferation => high G1 peak (60%), S(20%), G2/M (20%)
2. low proliferation =>
low G1 peak (40%) , S(40%) and (20%)

=>G2/mitosis is similar because it is time liited part of cell cycle.

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10
Q

How can you look at stages of cell cycle using fluorescence microscopy?

A 
Blue = DNA 
Red = y =tubulin 
green = CHEK2 
yellow = centrioles (y tubulin and CHEK2 co-localised)
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11
Q

What are 3 cell cycle checkpoints?

A

1) G1 (restriction point) = checks for DNA damage, cell size is big enough to be divided, metabolic/nutrient stores
=> cells re entering from G0 must also pass restriction check point.

2) G2 = when DNA commits to enter mitosis, DNA completely replicated, check if synthesis is completely done, check to see if DNA is damaged.
3) Mitosis= check for physical position of spindle, ensure they are aligned on spindle so can separate into 2 sister cells.

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12
Q

What two molecules are involved in control that ensures the strict alternation of mitosis and DNA replication?

A
  1. protein kinases = forms phosphodiester bonds , attach phosphate molecules
  2. phosphatases = break phosphodiester bonds
    => enables mitosis to happen when cell has the right number of chromosome and synthesis to only happen when mitosis is done.
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13
Q

What are 4 main phases of mitosis?

A
  1. prophase
    - nucleus becomes less definite
    -microtubular spindle apparatus assembles
    -centrioles migrate to poles
    =>prometaphase
    -nuclear membrane breaks down
    -kinetochores attach to spindle in nuclear region
  2. metaphase
    - chromosomes align in equatorial plane
  3. Anaphase
    -chromatids separate and migrate to opposite poles
  4. Telephase
    - daughter nuclei form
    =>cytokinesis
    -division of cytoplasm
    -chromosomes decondense
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14
Q

Where do external growth factors act within the cell?

A
  • G1 phase

- G0 cell would be activated by growth factor and pass restriction point and enter cell cycle.

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15
Q

How is active cyclin -CDK complex formed to phosphorylate specific substrates?

A
  1. Cyclin proteins expression is induced by growth factors.
  2. cyclin in a regulatory subunit (>20 genes) and when there is sufficient amount it binds to CDK.
  3. Active CDK - cylin complex formed which phosphorylates specific substrate proteins.
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16
Q

how are cylin- CDK regulated?

A
  1. cycles of synthesis (gene expression) and destruction (proteasome)
  2. post transcriptional modification by phosphorylation (may result in activation,inhibition or destruction)
  3. dephosphorylation
  4. binding of cylin -dependent kinase inhibitors (CDKIs)
17
Q

Retinoblastoma is a key substrate of G1 and G1/S cyclin -dependent kinases

A
  • Retinablastoma protein (RB)
    1. unphosphorylated RB binds to E2F transcription factor (preventing it from binding to promoters) DNA replication doesn’t occur so progression from G1 to S phase doesn’t occur.
    2. when cyclin D-CDK4 and Cyclin E-CDK2 are present they cause RB to become phosphorylated.
    3. When phosphorylated RB dissociates from E2F, so E2F is no longer repressed so it is able to bind to promoters of its target gene ,DNA polymerase, starting DNA replication.
18
Q

How is E2F dissociation from RB a positive feedback?

A
  • E2F dissociates it binds to to promoter of cyclin E

- so more Cyclin E made and moreE2F dissociates = positive feedback loop.

19
Q

how are different Cyclin -CDK involved in the cell cycle

A
  1. mitogens signal to the nucleus and via transcriptional activation make early genes
  2. expression of early genes drive expression of delayed genes which includes cyclin D, with increased expression of cyclin D, it forms active complexes with CDK 4/6.
  3. Cyclin-CDK4/6 complex is sufficient enough to allow hypophosphorylation of RB which causes RB binding to E2F.
  4. cylin E - CDK2 causes increased expression which leads to hyperphosphorylation, losing all ability to repress E2F, dissociated E2F binds to promoters of cyclin E increasing expression of cyclin E.
  5. This causes E2F responsive genes to be activated (synthesis phase).
  6. cyclin E- CDK2 complex phosphorylates and activates cyclin A-CDK2 (S phase) which activates Cyclin A -CDK1 (G2phase) which then activates cyclin B and CDK1 (M phase).
  7. At the end of mitosis dephosphorylation of RB which is mediated by PP1 phosphatase.
20
Q

DNA damage leads to…

A
  1. stop the cell cycle (cylin dependent kinase inhibitor)
  2. attempt DNA repair
  3. programmed cell death (apoptosis)
21
Q

How is TP53 phosphorylated?

A

Normally tumour suppressor gene is continually destroyed by proteosomes so barely any in cell.

  1. Mutagen causes DNA damage.
  2. DNA damage causes Kinase activation
  3. kinase activation causes phosphorylation of TP53, once its phosphorylated it can no longer be broken down by proteosomes.
  4. so TP53 accumulates which derives a number of different functions.
22
Q

What does accumulation of TP53 lead to ?

A
  1. expression of CKI cell cycle arrest.
  2. DNA repair , eg. excision repair.
  3. activates apoptosis
23
Q

What happens if tp53 loses its function?

A

=> TP53 loss of function mutations are amongst the most frequent in cancer.
=> opposite effect to what accumulation did.
1. prevent cell cycle arrest - faster growth
2. prevent apoptosis - do not die
3. Prevent DNA repair - more mutations = more heterogeneity, more adaptation , cancer progression.

24
Q

What is the aim of chemotherapeutics drugs?

A
  • act on cell cycle of cancer cells

- objective : stop proliferation, induce apoptosis

25
Q

How do S phase drugs work in chemotherapy?

A

by causing DNA damage

  1. 5-fluoruracial (prevents synthesis of thymidine)
  2. Cisplatin (binds to DNA causing damage and blocking repair)
26
Q

How do M phase drugs work in chemotherapy?

A 
by targeting the mitotic spindle 
1.  vinica alkaloids 
- stabilize free tubulin 
- prevent microtubule polymerization 
arrest cells in mitosis 
2.  paclitaxel (taxol)
-stabilize microtubules 
-preventing de-polymerisation 
-arrest cells in mitosis

=> Colchicine (similar mode of action to vinica alkaloids)

27
Q

What is the function of cyclins?

A
  • cyclins are regulatory subunits of CDK complexes that control cell cycle check points by phosphorylating and inactivating target gene. The cyclins associate with different CDKs to provide specificity of function at different times during the cell cycle.

molecular basis of disease (29 decks)

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