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MOLECULAR BASIS OF DISEASE > 2. MECHANISMS OF DISEASE I - CELL GROWTH & DIFFERENTIATION > Flashcards

2. MECHANISMS OF DISEASE I - CELL GROWTH & DIFFERENTIATION Flashcards

1
Q

What’s the difference between cell growth & cell differentiation?

A
  • Both cell differentiation & cell growth are processes that are involved in turning a zygote into a mature organism
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2
Q

What are the three main groups of disease related to cell growth & differentiation?

A
  1. DEVELOPMENTAL CONDITIONS
    - defects related to cell growth and/or differentiation
    - e.g neural tube defects
  2. NEOPLASIA & METAPLASIA
    - Neoplasia = uncontrolled cell growth
    - Metaplasia = transformation of a cell from one type into another
    - e.g tumours & cancers
  3. OTHER
    - e.g cardiac hypertrophy
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3
Q

What are the two main forms of cell growth?

A
  1. Hypertrophy

2. Hyperplasia

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4
Q

What is hypertrophy?

A
  • An increasein size, cells become bigger
  • More proteins, lipids, nutrients etc.
  • Increased protein synthesis is sufficient to cause increase in cell size
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5
Q

What is hyperplasia?

A
  • An increase in celll number due to more cells
  • Hyperplasia mainly caused by cell proliferation & cell division
  • Hyperplasia is more common than hypertrophy
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6
Q

How do extracellular signals interactwith the promoter?

A
  • Cell differentiation & cell growth are controlled by the integartion/combination of intracellular & extracellular signals
  • These signals converge onto the rpomter of a key gene involved in cell proliferation & differentiation
  • Promoters of these genes act as co-incidence detectors, decision can be made about whetehr or not to express gene & how much
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7
Q

What are the three classes of extracellular signals?

A
  1. PARACRINE - secreted locally (e.g neighbouring cell) which causes proliferation of different cell type
  2. AUTOCRINE - cell secretes it’s pwn ligand which it can then bind to
  3. ENDOCRINE - released systemically/ into the circulation for distant effects
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8
Q

What are mitogens & give examples?

A
  • Mitogens are extracellular signals that stimulate proliferation & promte cell survival
  • E.g growth factors (EGF, FGF), interleukins
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9
Q

Give an example of a signal which can inhibit & stimulate proliferation?

A
  • TNF Beta
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10
Q

Give an example of a signal which can inhibit/stimulate proliferation & promote differentiation?

A
  • Wnt ligands
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11
Q

What can TNF alpha induce?

A
  • TNF alpha can induce apoptosis
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12
Q

Describe the process by which extracellular signals induce gene expression

A
  1. Extracellular signal (GF) binds to receptor
  2. Activates signal trasnduction pathway
  3. Transcripton factors are activated via kinase cascade
  4. mRNA transcribed & proteins produced
  5. Proteins can remain in the cytoplasm or membrane, or return to nucleus to act as TF or nuclear protein
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13
Q

What are the 4 phases of the cell cycle?

A
  1. G1 PHASE - Growth phase, preparation for S phase. Responsive to Growth factors
  2. S PHASE - DNA synthesis occurs & chromosome replication
  3. G2 PHASE - growth & preparation for M phase, organelles & cytoplasm doubled
  4. M PHASE - Mitosis & cytokinesis
  5. G0 PHASE - rets phase where no cell division oocurs, state of quiescence
    - G0 & G1 phase = didploid
    - S phase = in between diploid & tetrapolid as cells are still replicating
    - G2 & M phase = after replication - tetraploid
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14
Q

What are the 5 phases of mitosis?

A
  1. PROPHASE - chromosmes condense, nuclues becomes less visible. Centrioles migrate to opposite poles & mitotic spindles form
  2. PROMETAPHASE - nuclear envelope breaks down & centromere attaches to mitotic spindle via kinetochore
  3. METAPHASE - chromosomes are at their most condensed, chromosomes align on equator known as metaphase plate, centrioles at opposite ends
  4. ANAPHASE - ssister chromatids sepaarte synchronously, daughter chromsomes migrate to oppsite poles
  5. TELOPHASE - chromsomes arrive at centrioles & decidense, nuclear envelope reforms
    - Cytokinesis - cytoplasmic division of daughter cells
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15
Q

How do cells become terminally differentiated?

A
  • Cells leave the cell cycle and are termed post-mitotic cells
  • Cell type specific gene expression results in changes in cell morphology & function
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16
Q

What are the two outcomes of quiesecent cells?

A
  • Quiescent cells have entered G0 phase meaning they no longer undergo cell division, so can have two outcomes:
    1. Terminally differentiate
    2. Re-enter cell cycle
  • Ultimate fate of cells is apoptosis
17
Q

What can flow cytometry show about DNA content?

A
  • Rate of division determined by number of cells in G1 relative to G2/M phase
  • G1 = diploid, G2/M phase = tetraploid
  • High n in G1 relative to G2/M = low rate of division
  • Lower/ equal n of cells in G1 relative to G2/M = high rate of division
18
Q

What are cell cycle checkpoints?

A
  • Cell cycle checkpoints are a strict set of controls which controls the alternation between DNA replication & mitosis
19
Q

What are the three cell cycle checkpoints?

A
  1. G1 CHECKPOINT (end of G1 before S phase)
    - Known as the restriction point, considered to be teh msot important.
    - Checks for DNA damage, metabollites & nutrients stores to ensure everything correct before replication
  2. G2 PHASE (end of G2 before M phase)
    - Checks DNA is correctly replicated to ensure enough chromsomal DNA for two daughter cells. Checks DNA damage before mitosis
  3. M PHASE CHECKPOINT
    - Checks chromosomes are correctly alligned on the spindle before metapahse to ensure correct number of chromsomes in daughter cells
20
Q

What are cyclin dependent kinases?

A
  • Cyclin dependent kinases (CDKs) are catalytic sub-units encoded by 10 gens.
    CDK must be bound to cyclins to be active & phosphorylate substrates of target proteins
21
Q

What are cyclins?

A
  • Cyclins are reguatory sub-units made up of more than 20 gens
  • Cyclins control the activation of CDKS
  • Different cyclins are produced durig different phases of the cell cycle & they bind to their corresponding CDKs
  • When there’s sufficient cyclin expression, it will form a complex with CDKS
22
Q

How is cyclin-CDK activity regulated?

A
  • Cyclins have a high rate of turnover, being degraded by the proteasome
  • Cyclins & CDKS can be phsophorylated or dephosphorylated, eitehr activating or inhibiting them
  • Binding of cyclin dependent kinase inhibitirs (CDI) to CDKs to cause cell cycle arrest
23
Q

What is retinoblastoma?

A
  • Retinoblastoma is a tumour suppressor gene
  • It’s a key substrate of G1/S phase CDKs
  • When unphosphorylated, retinoblastoma supresses E2F
24
Q

What is E2F?

A
  • E2F is a transcription factor involved in the trasncription of S phase related proteins such as DNA polymerase, thymidine kinase etc.
  • When retinoblastoma binds E2F, it prevents E2F from binding to the promoter of S phase related proteins meaning there’s no progression into the S phase
25
Q

Describe how retinoblastoma is phosphorylated

A
  • When retinoblastoma is phosphorylated, it cannot bind E2F & therefore no longer acts as a TF
  • Cyclin D-CDK 4/6 hypophosphorylates retionblastoma, allowing small E2F activity
  • E2F results in Cyclin E production, which then forms a complex with CDK 2
  • Cyclin E-CDK 2 hyperphsophorylates retionoblastoma, releasing E2F
  • There is positive feedback for Cyclin E & E2F, as E2F activity increases, more cyclin E is produced which in turn results in more E2F activity
26
Q

Describe the sequence of events in the cell cycle involving retinoblastoma

A
  1. Mitogens/growth factors act on G1 phase to cause EARLY GENE EXPRESSION
  2. EARLY GENE EXPRESSION causes expression of DELAYED GENES such as Cyclin D, CDK 4/6 & E2F
  3. Cyclin D levels increase and forms a complex with CDK 4/6.
  4. Cyclin D-CDK 4/6 HYPOPHOSPHORYLATES retinoblastoma, allowing some E2F activity
  5. Small amounts of E2F activity result in Cyclin E expression
  6. Cyclin E forms a complex with CDK 2.
  7. Cyclin E-CDK 2 HYPERPHOSPHORYLATES retinoblastoma, releasing E2F
  8. E2F activity remains high resulting in expression of S phase proteins, allowing progession into the S phase
  9. Sequential activation of cyclin-CDK complexes
    Cyclin E-CDK2 -> Cyclin A-CDK2 -> Cyclin A-CDK1 -> Cyclin B-CDK1
  10. Dephosphorylation of retinoblastoma by PP1
27
Q

What are the three responses to DNA damage?

A
  1. Cell cycle arrest - principally driven by CDK1 but also CHEK2
  2. DNA Repair - base excision, mismatch repair
  3. Apoptosis - driven by BCL2 & caspases
28
Q

What are the different cyclin-CDK complexes of the cell cycle?

A
  • G1 PHASE = Cyclin D-CDK 4/6
  • G1/S PHASE = Cyclin E-CDK2
  • S PHASE = Cyclin A-CDK2
  • G2 PHASE = Cyclin A-CDK1
  • M PHASE = Cyclin B-CDK1
29
Q

What is TP53?

A
  • TP53 is the tumour suppressor gene which is considered to be the ‘guardian of the genome’
  • Normally, TP53 levels are low or virtually zero due to degradation by the proteasome but it can be activated in response to DNA damage
30
Q

How does DNA damage result in TP53 activation?

A
  1. Mutagens/DNA damage cause kinase activation
  2. Kinases phosphorylate P53
  3. Phosphorylated P53 cannot be degraded/broken down by proteasomes
31
Q

What are the three effects of TP53 in response to DNA damage?

A
  1. Cell cycle arrest - through CDKI expression
  2. DNA repair - excision repair
  3. Apoptosis (if repair is not possible)
32
Q

What are the consequences of P53 mutations?

A
  • P53 is a tumour suppressor gene, so mutations can lead to a loss of function. P53 is no longer able to control cell proliferation & cannot suppress tumour debvelopment resulting in cancer
  • Loss of P53 mutation+
    1. NO CELL CYCLE ARREST = Faster growth/proliferation
    2. NO DNA REPAIR = Cancer cells accumulate mutaions and adapt to environment allowing cancer to progress
    3. NO APOPTOSIS = cells don’t die
33
Q

What are the two classes of chemotherapeutic drugs that act on the cell cycle used to treat cancer?

A
  1. S phase drugs

2. M phase drugs

34
Q

What are two examples of S phase drugs?

A
  • S phase drugs cause DNA damage so that the cells cannot progress into the S phase because of the G1/S phase checkpoint
    1. 5-FLUOROURACIL - prevents synthesis of thymidine
    2. CISPLATIN - binds to DNA causing DNA damage & blocks DNA repair
35
Q

What are two examples of M phase drugs?

A
  • M phase drugs target the mitotic spindle, so that the centromere cannot attach properly to mitotic spindle
    1. VINCA ALKALOIDS
    2. PACLITAXEL
36
Q

What is Vinca Alkaloid?

A
  • Vinca Alkaloids stabilise & binds to free/monomeric tubulin
  • PREVENT POLYMERISATION so that microtubules cannot form = no mitotic spindle formation
  • Cells are arrested in mitosis
37
Q

What is Paclitaxel?

A
  • Paclitaxel stabilises microtubules/polymerised tubulin
  • PREVENTS DEPOLYMERISATION of microtubules
  • Cells arrested in mitosis

MOLECULAR BASIS OF DISEASE (4 decks)

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