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Molecular Basis of Disease(Sem 4) > Mechanisms of Disease 1:Cell growth and Cell differentiation (Cellular Pathology) > Flashcards

Mechanisms of Disease 1:Cell growth and Cell differentiation (Cellular Pathology) Flashcards

Cellular Pathology

1
Q

What is cell growth?

A

Bigger organism means more cells. An increase in cell numbers

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2
Q

What is cell differentiation?

A

When cells stop growing and become more complex at end of growth

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3
Q

What is the meaning of cell potency?

A

This is the cell’s ability to differentiate into other cell types

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4
Q

What are the three categories of diseases due to cell differentiation and growth?

A
  • Developmental conditions

- Neoplasia/Metoplasia

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5
Q

What is an example of a developmental condition?

A

Neural tube defect - Spina bifida

neural tube does not close all the way

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6
Q

What is neoplasia and what can it cause?

A

new, uncontrolled growth of cells
replacement of one differentiated cell type with another mature differentiated cell type that is not normally present #
Cancer

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7
Q

What are two types of cell growth?

A

Hypertrophy

Hyperplasia

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8
Q

What is hyperplasia ?

A

More cells

Increased cell proliferation

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9
Q

What is hypertrophy?

A

Cells become bigger.
Caused by cells making more macromolecules, proteins and they become bigger
Increases protein synthesis is a big driver in cell size

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10
Q

What are differentiated cells also called ?

A

Post mitotic

They will show specific tissue type gene expression

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11
Q

What are the similarities between cell growth and cell differentiation?

A

They are both controlled by the integration of multiple signals
Intra and extracellular signals
Growth /inhibitory factors

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12
Q

What are co-incidence detectors?

A

This is when a neuron encodes information by detecting close spatial signals
Due to promoters found on important genes

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13
Q

What are extracellular signals?

A

They are ligands which bind on receptor leading to intracellular cascade

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14
Q

What are the three classes of extracellular signals ?

A

Paracrine
Autocrine
Endocrine

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15
Q

Describe Paracrine

A

This is produced locally to stimulate proliferation of a different cell
(Cell to cell)

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16
Q

Describe Endocrine

A

This is hormones released for distant effects

hormone signalling

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17
Q

Describe Autocrine

A

Produced by a cell that will also express appropriate cell surface receptor
(hormonew signalling binds on SAME cells)

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18
Q

How are extracellular signals involved in cell growth and differentiation?

A

Proteins that stimulate proliferation and promote survival-
Mitogens (Growth factors/interleukins)

Induce differentiation and inhibit proliferation

Induce apoptosis (TNF family)

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19
Q

Overview how extracellular signalling will induce gene expression

A
  1. A growth factor will bind to its receptor
  2. This activates signal transduction via a kinase cascade
  3. This activates transcription factors in the nucleus
  4. Transcription factors will drive transcription of downstream genes
  5. Creates an mRNA which is exported to cytoplasm
  6. Protein synthesis and translation will take place
  7. Proteins are made which will remain in cytoplasm and exert their functions.
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20
Q

What are the phases of the cell cycle ?

A

M ,G1,S ,G2

21
Q

What is the M phase ?

A

This is mitosis in which the cell divides to give two daughter cells

22
Q

What is meant by interphase?

A

These are the phases of the cell cycle which are not mitosis

23
Q

What is the G1/G2 phase ?

A

These are the two gap phases

G1-The cell will increase in size and cellular contents will become duplicated
G2-The cell will grow more
Organelles and proteins will develop to prepare for cell division

24
Q

What is the S phase ?

A

This is the synthesis phase in which the genetic material will replicate

25
Q

What are cells which leave the cell cycle following mitosis referred to as ?
What can happen to these cells

A

These are quiescent cells (In phase G0)

  • They can become permanently differentiated and ultimately will undergo apoptosis
  • They can re-enter the cell cycle at G1(if they get a stimulus )
  • They can remain in G0 forever
26
Q

What is G0?

A

This is when cells will exit the cell cycle at G1 and enter a resting state.They will perform its function but not actively divide

27
Q

Outline the chromosome numbers throughout the cell cycle

How can this be used ?

A

Following mitosis
2N (diploid )-Human genome is diploid
Following S phase = (G2)
4N tetraploid

We can check the number of chromosomes and measure a cells proliferation

28
Q

What is FACS?

A

This is fluorescent-activating cell sorting
It is a method of flow cytometry

Can be used to measure DNA content
DNA stain applied and FACS can measure DNA content of every cell in population

Plot a graph which corresponds to the stage of cycle

29
Q

How would FACS graph be different between low proliferation and high proliferation?

A

In high rate of division the proportion of cells in G1 will decrease whilst population in S phase will increase.

(High S-phase implies large number of mitotic cycles per time )

30
Q

What are the different colours in fluorescence microscopy and what do they show?

A

Blue -DNA
Red -Gamma tubulin
( required for microtubule function)
Green -CHEK2
(Checkpoint kinase 2 is a tumour suppressor gene)
Yellow -Centrioles
(Can also mean that gamma-tubulin and CHEK2 are in the same place-colocalised)

31
Q

What does ploidy mean ?

A

This is the number of chromosome sets in a cell or organism.
E.g.-Haploid- One set
Diploid-Two sets

32
Q

What are the 4 stages of mitosis ?

A

Prophase
Metaphase
Anaphase
Telophase

33
Q

Outline the four stages in detail

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
34
Q

Why are controls involved the cell cycle?

A

Specific protein kinases and phosphatases and they are important to ensure that mitosis only occurs when cells have the right amount of chromosomes and synthesis only happens when cell completes mitosis

35
Q

What are the control checkpoints ?

A

Restriction point -Near G1)
-This checks to ensure DNA not damaged ,cell size ,metabolite and nutrient stores

G2 M phase point
-To ensure synthesis has completed and no DNA damage/DNA fully replicated

Chromosomes are aligned on spindle
-When the mitotic spindle separates the right number of each chromosome will go to each cell

36
Q

What are kinases and phosphotases ?

A

Kinases -Add kinase

Phosphatase-Remove phosphate

37
Q

Where do external growth factors act ?

A

They will act within G1 phase upstream to restriction point

Activates the cell and allows it to pass through restriction point

38
Q

What are the kinases involved in regulating the cell cycle?

A

CDKs
Cyclin-dependant kinases
There are 10 genes which encode CDK proteins
more than 20 genes encoding cyclins

The expression of cyclins is controlled by mitotic factors

39
Q

Outline how CDKS work

A
  1. There are signals which will cause expression of cyclins
  2. When there is sufficient amount of cyclin it will form a complex with CDK
  3. This is an active kinase complex which phosphorylates specific substrates
40
Q

Outline regulation of Cyclin-CDK

A
  • Cycles of synthesis (gene expression) and destruction (by proteasome)
  • Post translational modification by phosphorylation
  • The phosphoylation may result in activation, inhibition or destruction
  • Dephosphorylation
  • Binding of cyclin-dependent kinase inhibitors (CDKIs)
41
Q

How do CDKIS work?

A

They can bind to the Cyclin-CDK complexes and inhibit them

42
Q

What is a substrate of CDK?

Explain how it works

A

Retinoblastoma protein (RB)
Key substrate of cylin dependent cyclase
G1/G1-S phase of cell cycle

  • Normally unphosphorylated RB binds to E2F (transcription factor) which prevents E2F binding to gene promoters preventing transcription (no stimulation of S-phase proteins)
  • When RB is in presence of Cyclin D-CDK4 and Cylin E-CDK2,its phosphorylated which means RB dissociates from E2F.

E2F is no longer supressed.

E2F also binds to promotor of Cylin E meaning drives positive feedback loop for
Cyclin E-CDK2 expression.

43
Q

What do mitogens do?

A

These will act in the G1 phase which will signal to the nucleus and through transcription will cause expression of “early genes “.These include transcription factor and will cause expression of delayed genes.

Delayed genes contain Cylin D which can form active complexes with CDK4/6.

Cyclin +CDK will cause hypo phosphorylate to the RB.
Some expression of E2F which will increase Cylin E expression
Cylcin E-CDK causes second level phosphorylation of RB which loses all repressive ability.

E2F remains high

This will then activate E2F responsive genes required for S phase.

Cylin E-CDK2 activates

44
Q

Explain the sequence of events triggered by mitogens (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 (unactivated ) 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.

45
Q

What will happen if there is DNA damage ?

Outline three processes

A

This will trigger cell cyle arrest and apoptosis.

1.Stop the cycle through Cyclin dependant kinase inhibitors

2.Attempt DNA repair (Mismatch repair, nucleotide/base excision enzymes )
Enzymes that cleave the bond between deoxyribose and a modified or mismatched DNA

3.Programmed Cell death (if repair is not possible)
-BCL2 family )
blocks the apoptotic death of some cells such as lymphocytes

Caspases-are a family of protease enzymes playing essential roles in programmed cell death.

46
Q

Describe the role of TP53 with DNA Damage

A

Tumour protein 53
If the DNA is completely fine TP53 will be destroyed by proteasome.

If DNA is damaged -
(Mutagen binds )
1.This is detected and causes activation of protein kinases which phosphorylate TP53.
(CAN NO LONGER BE DESTROYED BY PROTEOSOME)

  1. TP53 will cause expression of CDKI leading to cell cycle arrest
  2. Also activates DNA repair causing repair
  3. If it can not be fixed it will cause cell death.
47
Q

Describe TP53 in cancer

A

A loss of TP53 due to loss of function mutations are very frequent in cancer

This means prevents cell cycle arrest
Prevents apoptosis
Prevents DNA repair

This causes faster growth, do not die and this can cause more mutations

Heterogeneity
More adaption
More progression

48
Q

How is chemotherapy involved in the cell cycle?

A

It will stop proliferation and induce apoptosis.

S phase drugs cause DNA Damage

  • 5-fluorouracil (stops thymine synthesis )
  • Cisplatin (binds to DNA causing damage and blocking repair
49
Q

Outline M pahse drugs and how they work .

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

Molecular Basis of Disease(Sem 4) (28 decks)

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