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Clinical Pathology > Cellular Growth Regulation > Flashcards

Cellular Growth Regulation Flashcards

1
Q

What are the three considerations for cell growth?

A
  1. Growth of population of cells
  2. Growth at cellular level (cell cycle)
  3. Loss of cells by programmed cell death (apoptosis)
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2
Q

Elaborate on ‘growth of a population of cells’

A

Distinguish between cell hyperplasia (increase in cell number) and cell hypertrophy (increase in cell size).
Both are dependent on intracellular and extracellular signals e.g checks on cellular physiology, growth factors, inhibitory factors, cell adhesions.

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3
Q

Give examples of these intracellular and extracellular signals

A

Checks on cellular physiology, growth factors, inhibitory factors and cell adhesion

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4
Q

Elaborate on ‘growth at the cellular level’

A

Cell growth = increase in cell size and or cell division
Cell cycle phases= G1, S, G2 and M
Progression is controlled at three key checkpoints (restriction points)

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5
Q

What is G1?

A

Part of interphase. Cell synthesises mRNA and proteins (histones) for DNA replication. Need sufficient nucleotides.

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6
Q

What is S phase?

A

Second part of interphase. DNA replication (incorporation of thymidine). Semi conservative replication.

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7
Q

What is G2?

A

Last part of interphase. Rapid cell growth and protein synthesis for mitosis.

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8
Q

What is M phase?

A

Mitosis. Consists of prophase, prometaphase, metaphase, anaphase, telophase, cytokinesis.

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9
Q

Elaborate on ‘loss of cells by programmed cell death’

A

Apoptosis = coordinated program of cell dismantling ending in phagocytosis. NOT NECROSIS
Occurs during normal development (e.g separation of digits, involution, immune system and nervous system development)
Can occur in response to DNA damage and viral infection.

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10
Q

Give examples when apoptosis occurs during normal development

A

Separation of digits, involution, immune and nervous system development

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11
Q

What would happen to cells if they’re infected by a virus?

A

Apoptosis

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12
Q

What are growth factors, cytokines and interleukins?

A

These are proteins that can:

  1. Stimulate cell proliferation (mitogens) and maintain survival e.g EGF, FGF, IL2, IL4, PDGF, IGF1
  2. Stimulate differentiation and inhibit proliferation e.g TGFB
  3. Induce apoptosis e.g TNFa and other members of TNF family
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13
Q

What are the three classes of growth factors, cytokines and interleukins?

A
  1. Paracrine
  2. Endocrine
  3. Autocrine
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14
Q

What is the paracrine system?

A

Produces proteins locally that stimulate proliferation of a different cell type that has the appropriate cell surface receptor

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15
Q

What is the endocrine system?

A

Proteins that released into bloodstream and affect distant targets by binding to their receptors

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16
Q

What is the autocrine system?

A

Proteins produced by a cell that acts on the same cell that released the protein. Needs to have appropriate receptors.

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17
Q

Explain the cell population growth graph

A
  1. Lag phase = adaptation to new conditions. They are maturing and unable to divide just yet. Are metabolically active.
  2. Log phase = Population of cells divide exponentially. Signalled by growth factors (e.g PDGF). They have plenty of nutrients to survive - no limiting factors
  3. Stationary phase = Population size now remains constant. Some cells continue to divide whilst others die (e.g due to TGFB)
  4. Death phase = Exponential decrease in population of cells. Signalled by factors (e.g TNFa)
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18
Q

Explain the cell population growth on the slide

A
  1. Addition of PDGF causes an increase in population of cells (increase cell division/growth)
  2. Removal of PDGF prevents further growth of these cells so plateau
  3. Adding growth inhibitors like TGFB prevents proliferation causing plateau
  4. Adding death signal like TNFa causes apoptosis hence more cells die so population of cells decrease.
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19
Q

What can quiescent cells do?

A
  1. Re-enter cell cycle and divide

2. Terminally differentiate to form post mitotic tissue. Cell shedding and apoptosis e.g gut epithelial cells

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20
Q

What are the key concepts of DNA replication?

A
  1. DNA is replicated semiconservatively (DNA molecules consist of one parental strand and one new strand)
  2. New DNA strand is synthesised in 5’-3’ direction from deoxynucleotide triphosphate precursors at a replication fork by a multienzyme complex (replication machine)
  3. Complementary base pairing and proof reading enzyme in DNA polymerase
  4. Leading strand requires a single RNA primer and synthesis occurs continuously; lagging strand needs multiple RNA primers, giving rise to okazaki fragments which are ligated together after the RNA primers are removed.
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21
Q

What happens in prophase?

A
  1. Nucleus becomes less defined
  2. Microtubular spindle apparatus assembles
  3. Centrioles migrate to poles
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22
Q

What happens in prometaphase?

A
  1. Nuclear membrane breaks down

2. Kinetochores attach to spindle in nuclear region

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23
Q

What are kinetochores?

A

Complex protein on the centromere that attaches to spindles.

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24
Q

What happens in metaphase?

A

Chromosomes align single file at the equator of the cell

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25
Q

What happens in anaphase?

A

Sister chromatic separate and migrate to opposite poles

26
Q

What happens in telophase?

A

Daughter nuclei form

27
Q

What happens in cytokinesis?

A
  1. Division of cytoplasm

2. Chromosomes decondense

28
Q

What is 5-fluorouracil?

A

Analogue of thymidine. It blocks thymidylate synthesis in S phase.
Used to treat some cancers. Basically prevents DNA replication.

Bromodeoxyuridine is also an analogue which may be incorporated into DNA and detected by antibodies to identify cells that have passed through the S- phase (used in research)

29
Q

What is Colchicine?

A

M- phase active drug. Stabilises free tubulin, preventing microtubule polymerisation and arresting cells in mitosis. It is used for karyotype analysis.

30
Q

What is Vinca alkaloids?

A

M-phase active drug that affects microtubules polymerisation

31
Q

What is Paclitaxel?

A

Stabilises microtubules and prevents depolymerisation

32
Q

What happens to cell size during interphase?

A

Cells grow in size because most of the macromolecules are synthesises continuously throughout interphase.

33
Q

What are the two pathways the daughter cells can take?

A
  1. Can continue in the cell cycle and carry on dividing

2. Can withdraw from the cell cycle (quiescent cells - aren’t dividing and aren’t preparing for division) - G0

34
Q

Name the 4 drugs used to treat cancer

A
  1. Fluorouracil
  2. Paclitaxel,
  3. Vinca alkaloids
  4. Tamoxifen
35
Q

What are cell cycle checkpoints?

A

Controls which ensure strict alteration of mitosis and DNA replication.
Involves specific protein kinases and phosphatases.

37
Q

What is the main site of control for cell growth?

A

G1 because this is when cells are responsive to growth factors, inducing them to either proliferate or not.

38
Q

What controls cell cycle progression?

A

Cyclin dependent kinase activity

39
Q

What is the genetic make up of CDK?

A

Encoded by 10 genes.

Catalytic subunit. Adds phosphate groups to substrate

40
Q

What is the genetic make up of cyclin?

A

Encoded by over 20 genes. It is the regulatory subunit. It binds to CDKs to activate them.

41
Q

How are substrates involved in cell cycle?

A

Active Cyclin-CDK complexes phosphorylates specific substrates.

42
Q

How is Cyclin-CDK activity regulated?

A
  1. Cyclical synthesis by gene expression. Destroyed by proteasome.
  2. Post translational modification by phosphorylation - depending on site of modification, it can cause activation, inhibition or destruction
  3. Dephosphorylation
  4. Binding of cyclin-dependent kinase inhibitors
43
Q

What is the retinoblastoma (RB/pRB) protein?

A

It is a tumour suppressor protein.

Prevents excessive cell growth by inhibiting the cell cycle until the cell is ready to divide.

44
Q

What is the importance of the retinoblastoma in the cell cycle?

A
  1. Unphosphorylated RB binds to E2F (to prevent stimulation of S-phase protein expression)
  2. Cyclin D-CDK4 and Cyclin E-CDK2 phosphorylate RB - this causes dissociation RB and E2F, allowing E2F to be active and act as a transcription factor.
45
Q

What are the effects of E2F as a transcription factor?

A

Stimulates expression of more cyclin E and S phase proteins e.g DNA polymerase, thymidine kinase, PCNA etc. DNA replication starts.

46
Q

What are cyclin dependent kinase inhibitors?

A

These inhibit cycling dependent kinases. There are 2 families.

  1. CDK Inhibitory protein/ Kinase inhibitory protein (CIP/KIP)/ CDKN1
  2. Inhibitors of Kinase 4 family (INK4)/CDKN2
47
Q

Explain CIP/KIP/CDKN1

A
  1. Expression of this family weakly stimulated by TGF B and strongly by DNA damage (involving TP53)
  2. Inhibit all other CDK-cyclin complexes (late G1, G2, M)
  3. Are gradually sequestered (isolated/destroyed) by G1 CDKs allowing activation of later CDKs (this is regulation)
48
Q

Explain inhibitor of kinase 4 family (INK4)/CDKN2

A
  1. Expression is stimulated by TGFB

2. Specifically inhibit G1 CDKs (e.g CDK4 - activated by growth factors)

49
Q

How do growth factors induce cyclin expression?

A
  1. Growth factor binds to receptor on the surface
  2. This signals transducers
  3. These affect the nucleus via kinase cascade by waves of transcription factor activation
  4. Then genes are transcribed to form mRNA and then translated to from proteins
50
Q

What are the three cell cycle checkpoints?

A
  1. Restriction point = ensure DNA isn’t damaged, cell size is correct, sufficient nutrient stores
  2. S phase= Ensure DNA is completely replicated, and isn’t damaged
  3. M phase = Ensure chromosomes are aligned correctly on spindles
51
Q

What are the sequence of events triggered by growth factors?

A
  1. Growth factor signalling activates early gene expression (transcription factors - FOS, JUN, MYC)
  2. Early gene products stimulate delayed gene expression (includes Cyclin D, CDK2/4 and E2F transcription factors)
  3. E2F sequestered by binding to unphosphorylated RB protein
  4. G1 Cyclin-CDK complexes hypophosphorylates RB and then G1/S cyclin-CDK complexes hyperphosphorylates RB releasing E2F
  5. E2F stimulates expression of more cyclin E and S-phase proteins e.g DNA polymerase, thymidine kinase, proliferating cell nuclear antigen etc.
52
Q

What are the switches on S-phase Cyclin CDK and G2/M cyclin-CDK complexes?

A

They build up in inactive forms. These switches are activated by post translational modifications or removal of inhibitors, driving the cell through S phase and mitosis.

53
Q

What happens if DNA damage is detected at checkpoints?

A

It triggers cell cycle arrest or apoptosis.

54
Q

What are the steps when checkpoints detect DNA damage?

A
  1. Stop the cycle via cyclin dependent kinase inhibitors and CHEK2
  2. Attempt DNA repair by nucleotide or base excision enzymes, mismatch repair
  3. Programmed cell death if repair impossible via BCL2 family and caspases
55
Q

What is the role of TP53 in the response to DNA damage?

A
  1. DNA mutation due to mutagen causes DNA damage
  2. This activates kinases
  3. Kinases phosphorylate TP53 (so now TP53 can’t be degraded by proteasome)
  4. Phosphorylated TP53 activates DNA repair by excision repair; causes expression of cyclin dependent kinase inhibitors (CIP/KIP) to cause cell cycle to arrest. If repair not possible, then it causes apoptosis.
56
Q

What is the importance of growth factors binding?

A

They induce gene expression

57
Q

What is the key substrate of G1/S phase cyclin dependent kinases?

A

RB. They phosphorylate RB in the absence of inhibition by CKI. The expression of these inhibitors is regulated by TP53 and TGFB

58
Q

What is the expression of CKI regulated by?

A

TP53 (activates CDNK1) and TGFB (weakly activates CDNK1; fully activates CDNK2)

59
Q

What is the importance of E2F being released?

A

It stimulates expression of genes requires for S phase

60
Q

What is needed for DNA replication?

A

You need expression of S-phase cyclin-CDK complexes.

61
Q

What happens after DNA is replicated correctly?

A

G2/M cyclin-CDK complexes cause cell to enter mitosis. If chromosomes are aligned on spindle then exit from mitosis is triggered

62
Q

What happens if the process of correct DNA replication fails?

A

TP53 initiates apoptosis.

Clinical Pathology (3 decks)

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