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MBD > Mechanisms of Disease I > Flashcards

Mechanisms of Disease I Flashcards

1
Q

How does a zygote turn into a mature multicellular organism?

A

Cell growth and differentiation are the basic mechanisms responsible for turning a zygote into a mature multicellular organism

  • Cell growth = a bigger organism more cells
  • Differentiation = cells become complex (usually) an end to growth
  • Cell growth precedes differentiation, but with some overlap
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2
Q

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

A

• Developmental conditions

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

• Neoplasia (and metaplasia)
- E.g. cancer, tumours

• Others, e.g. cardiac hypertrophy

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3
Q

What are the 2 main forms of cell growth?

A
  • hypertrophy (bigger cells)

* hyperplasia (more cells) - most common

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4
Q

Hypertrophy

A
  • Hypertrophy is simply cells growing bigger
  • More proteins, more membrane etc etc.
  • Elevated protein synthesis is a big driver of increased cell size
  • The heart is a classic example
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5
Q

Hyperplasia

A
  • Hyperplasia – more cells – is caused by cell division, or proliferation
  • example is the cell cycle
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6
Q

Differentiation

A

– Exit from the cell cycle
• Differentiated cells are “post-mitotic”
– A program of cell type-specific gene expression
– Cell morphology and function changes
diagram

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7
Q

Is there anything in common with Hypertrophy and Hyperplasia?

A

• Yes – 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.)
• Signals converge on the promoters of key genes
– Promoters act as “co-incidence detectors”
– Express gene YES/NO? How much?

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8
Q

Extracellular Signals Recap

A

(RECAP)
• Ligand – Receptor – Intracellular cascade
• Three broad classes:
• Paracrine: produced locally to stimulate proliferation of a different cell type that has 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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9
Q

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. TGF-beta
  • Can do either, e.g. Wnt ligands

• Induce apoptosis, e.g. TNFα and other members of the TNF family

diagram

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10
Q

Phases of the cell cycle

A

diagram

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11
Q

FACs analysis of cell DNA Content

A

If a DNA stain is applied, FACs can measure the DNA content of every cell in a population - diagram 1 +2

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12
Q

Fluorescence Microscopy

A 
Blue= DNA
Red = γ-tubulin 
Green = CHEK2
Yellow = centrioles
(γ-tubulin and CHEK2 colocalised)

diagram

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13
Q

Revision mitosis slides

A
  • Prophase (1)
  • Nucleus becomes less definite
  • Microtubular spindle apparatus assembles
  • Centrioles migrate to poles
  • Prometaphase
  • Nuclear membrane breaks down
  • Kinetochores attach to spindle in nuclear region
  • Metaphase (2)
  • Chromosomes align in equatorial plane
  • Anaphase (3)
  • Chromatids separate and migrate to opposite poles
  • Telophase (4)
  • Daughter nuclei form
  • Cytokinesis
  • Division of cytoplasm
  • Chromosomes decondense
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14
Q

Cell cycle checkpoints

A

Controls (involving specific protein kinases and phosphatases) ensure the strict alternation of mitosis and DNA replication.
diagram

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15
Q

CYCLIN-DEPENDENT

KINASES (CDK)

A

diagram

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16
Q

Regulation of Cyclin-CDK activity

A

• Cycles of synthesis (gene expression) and
destruction (by proteasome)
• Post translational modification by phosphorylation
• May result in activation, inhibition or destruction
• Dephosphorylation
• Binding of cyclin-dependent kinase inhibitors (CDKIs)

17
Q

RETINOBLASTOMA

PROTEIN (RB)

A

diagram

18
Q

SEQUENTIAL ACTIVITIES

IN THE CYCLE

A

diagram

19
Q

Revision slide -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.
20
Q

Checkpoint reminder - What if there is DNA damage?

A

diagram

DNA damage triggers cell cycle arrest or apoptosis

21
Q

ROLE OF TP53

A

diagram

22
Q

TP53 AND CANCER

A

• TP53 loss-of-function mutations are amongst the most frequent in cancer
– Prevent cell cycle arrest - faster growth
– Prevent apoptosis - don’t die
– Prevent DNA repair - more mutations = more heterogeneity, more adaption, cancer progression

23
Q

Chemotherapy pt 1

A

CHEMOTHERAPY
• Traditional chemotherapeutic drugs act on the cell cycle
– Objective: stop proliferation, induce apoptosis
• S-phase drugs cause DNA damage, e.g.
– 5-fluorouracil (prevents synthesis of thymidine)
– Cisplatin (binds to DNA causing damage and blocking repair)

24
Q

Chemotherapy pt 2

A
  • M-Phase drugs target the mitotic spindle
  • Vinca alkaloids
  • stabilize free tubulin
  • prevent microtubule polymerization
  • arrest cells in mitosis
  • Paclitaxel (Taxol)
  • stabilizes microtubules
  • preventing de-polymerization
  • arrests cell in mitosis
  • Not just cancer: colchicine (similar mode of action to vinca alkaloids) is used for immune-suppression
25
Q

revision slides- summary of key steps

A

• Growth factors binding to receptors induce gene expression
• G1 and G1/S Cyclin-CDK complexes phosphorylate RB in the absence of inhibition by CKIs (expression of these is regulated by TP53 or TGF-beta)
• E2F released, stimulating expression of genes required for S-phase
• Cell replicates DNA (expression of S-phase Cyclin-CDK complexes)
• If all DNA replicated, G2/M Cyclin-CDK complexes cause cell to enter
mitosis. If chromosomes aligned on spindle, exit from mitosis is triggered
• If process fails, TP53 initiates apoptosis

MBD (29 decks)

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