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CellularPathologyCOPY-aimen n-use this > Cellular Growth Regulation (Mechanisms of Disease I) > Flashcards

Cellular Growth Regulation (Mechanisms of Disease I) Flashcards

1
Q

What are the general considerations for cell growth?

A
  1. Growth at cellular level (cell cycle)
  2. Growth of a cell population
  3. Loss of cells via apoptosis
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2
Q

What are the 2 ways a cell population can grow?

A

Distinguish between:

  • increase in cell numbers (hyperplasia)
  • increase in cell size (hypertrophy)
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3
Q

What is the growth of a cell population dependent upon?

A

Intracellular and Extracellular signals

checks on cellular physiology, growth factors, inhibitory factors, cell adhesion

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4
Q

What is cell growth?

A

Cell growth = increase in size and number(cell division)

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5
Q

What are the phases of the cell cycle?

A

Cell cycle phases (G1, S, G2, and M)

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6
Q

How is the cell cycle mediated?

A

Progression throughout the cell cycle is controlled at 3 key checkpoints (restriction points)

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7
Q

What is apoptosis?

A

Coordinated, programmed cell dismantling that ends in phagocytosis
-Distinct from necrosis

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8
Q

When does apoptosis occur?

A
  • Normal development (e.g. separation of the digits, immune and nervous system development)
  • DNA damage + viral infection
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9
Q

Outline the role of growth factors, cytokines and interleukins

A

These are proteins that:

  • Mitogens = Stimulate proliferation + maintain survival
  • Stimulate differentiation + inhibit proliferation e.g. TGFβ
  • Induce apoptosis e.g. TNFα
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10
Q

How are proliferation-stimulating proteins named?

A

Usually named after originally identified target e.g. EGF, FGF, Interleukins (IL2 & IL4), NGF

but see also:
PDGF (platelet-derived GF) IGF1 (Insulin-like GF – the main effector of pituitary growth hormone)

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11
Q

What are the broad 3 classes of growth factors, interleukins and cytokines?

A
  • paracrine
  • autocrine
  • endocrine
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12
Q

What is meant by paracrine?

A

Paracrine: produced locally to stimulate proliferation of a different nearby cell type that has the appropriate cell surface receptor

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13
Q

What are endocrine signlas?

A

Endocrine: like conventional hormones, released systemically for distant effects

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14
Q

What is meant by autocrine signalling?

A

Autocrine: produced by a cell that also expresses the appropriate cell surface receptor

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15
Q

What is the effect of PDGF on the cell cycle?

A

PDGF - platelet derived growth factor

PDGF presence: Cells start entering cell cycle and proliferating
PDGF no longer available: cells stop dividing = plateau

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16
Q

What is the role of TGFβ in the cell cycle?

A

TGFβ - transforming growth factor beta

Causes proliferation and induction into cell cycle

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17
Q

How does TNF𝛼 affect the cell cycle?

A

TNF𝛼 - Tumor necrosis Factor
Eventually cells receive death signal and enter apoptosis
Cell no. decreases

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18
Q

Outline what occurs during interphase of the cell cycle

A

Cells grow in size as most macromolecules are synthesized continuously throughout interphase

Occurs after mitosis

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19
Q

When do cells enter G0 phase?

A

When cells don’t receive growth factors(FGF) , they become quiescent cells (remain indefinitely in G0)

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20
Q

How do quiescent(G0) cells re-enter the cell cycle?

A

Re-enter cell cycle when exposed to growth factors

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21
Q

How can we identify the no. of cells present during the cell cycle?

A

Use Fluorescence Activated Cell Sorter Analysis of Cell DNA Content

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22
Q

How does Fluorescence Activated Cell Sorter Analysis of Cell DNA Content work?

A
  • Cellular DNA is labelled with a fluorescent dye

- The dye is read by a laser which tells us the DNA content present ∴ cell number

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23
Q

What result would fluorescence show for cells that grow slowly

A

Cells that grow slowly will show a higher G1 peak as most cells are still in that phase

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24
Q

For fast growing cells, what would the fluorescence results show?

A

Fast cell division = less cells in G1 phase (lower first peak) as cells are progressing through the cell cycle

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25
Q

Outline the stages of DNA replication

A
  1. DNA replicated semiconservatively
    (daughter cells inherit one parental and one new strand)
  2. New DNA synthesized in 5’-3’ direction from
    deoxynucleotide triphosphate precursors at a replication
    fork by a multienzyme complex (a replication machine)
  3. Fidelity is determined by base pairing (A=T, G≡C) and
    presence of a proof reading enzyme in DNA polymerase
  4. Synthesis of new DNA strand uses an RNA primer and
    occurs continuously on leading strand and
    discontinuously on trailing strand
    (giving rise to Okazaki fragments, which are ligated
    together after removal of the RNA primer)
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26
Q

What are the main stages of Mitosis?

A 
1.  Prophase
Prometaphase
2. Metaphase
3. Anaphase
4. Telophase

Cytokinesis

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27
Q

Explain what happens during prophase

A
  • Chromosomes condense
  • Microtubular spindle apparatus assembles
  • Centrioles migrate to poles
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28
Q

What happens in prometaphase?

A
  • The nuclear membrane breaks down

- Kinetochores attach to spindle in nuclear region

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29
Q

Describe the events of Metaphase

A

Chromosomes align along the cell equator

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30
Q

Explain what occurs during anaphase

A

Chromatids are pulled apart to opposite poles of the cell

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31
Q

What happens during telophase?

A

Daughter nuclei form

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32
Q

What is cytokinesis?

A

Division of cytoplasm

Chromosomes decondense

33
Q

Name drugs that act on the S-phase of the cell cycle

A
  • 5-Fluorouracil

- Cisplatin

34
Q

Explain the role of 5-Fluorouracil on the S-phase of the cell cycle

A

5-Fluorouracil is an analogue of thymidine, blocks thymidine synthesis (needed for S phase DNA replication)

35
Q

Which drugs act on the M-phase of the cell cycle?

A
  • Colchicine
  • Vinca alkaloids
  • Paclitaxel (Taxol)
36
Q

What is the role of Vinca alkaloids?

A
  • stabilize free tubulin
  • prevent microtubule polymerization
  • arrest cells in mitosis
37
Q

What is the effect of Paclitaxel(Taxol) on M-phase?

A
  • Stabilises polymerised microtubules
  • Prevents depolymerisation
  • Arrests cell in mitosis
38
Q

What treatment uses drugs that act on the M-phase of the cell cycle?

A

5-Fluorouracil, Paclitaxel, Vinca alkaloids and Tamoxifen are used in treatment of cancer

39
Q

What are cell cycle checkpoints?

A

Cell cycle checkpoints are Controls (involving specific protein kinases and phosphatases) that ensure cell alternates between mitosis and DNA replication

40
Q

What are protein kinases?

A

proteins that phosphorylate proteins to activate them

41
Q

What are phosphatases?

A

Enzymes that removes phosphate groups from proteins

42
Q

What are mitogens?

A

A protein that induces a cell to begin cell division

43
Q

What other regulations are in place to ensure correct cell cycle functioning?

A
  • Cells respond to the extracellular environment(mitogens) only during G1 phase
  • Once cells enter S phase, they are unresponsive to extracellular signals
44
Q

What is the purpose of cyclin-dependent kinase activity?

A

Active Cyclin-CDK complex phosphorylates its substrate to control cell cycle progression

45
Q

How does a cyclin-dependent kinase activity regulate the cell cycle?

A

Cyclin-CDK bind and this active kinase complex binds to and phosphorylates its specific substrate protein

46
Q

How is cyclin-CDK activity itself regulated?

A

Cyclins = Cyclical synthesis (gene expression) + destruction (by proteasome)

Cyclins are regulated by post-translational modification (phosphorylation)
= activation/inhibition/destruction
+Regulated by Dephosphorylation

CDKIs bind + inhibit Cyclin-CDK complex

47
Q

What is the retinoblastoma Protein?

A

Rb protein = a key substrate of G1 and G1/S CDKs

48
Q

Explain the role of retinoblastoma protein on the cell cycle

A
  1. Unphosphorylated RB binds E2F (TF), preventing it from stimulating S-phase protein expression.
  2. Released E2F stimulates expression of more Cyclin E and S-phase proteins (e.g. DNA polymerase)
  3. DNA replication starts.
49
Q

What are the 2 families of CDK inhibitors?

A
  1. CDK Inhibitory Protein/Kinase Inhibitory Protein (CIP/KIP)
    family
    (now called CDKN1)
  2. Inhibitor of Kinase 4 family (INK4) (now called CDKN2)
50
Q

How are CDKN1 (CIP/KIP) expressed?

A

Expression of members of this family stimulated weakly by TGFβ and strongly by DNA damage (involving TP53)

Inhibit all other CDK-cyclin complexes (late G1, G2 and M)
Are gradually sequestered by G1 CDKs thus allowing activation of later CDKs

51
Q

How do CIP/KIP CDKN1 inhibit CDKs?

A

Inhibit all other CDK-cyclin complexes (late G1, G2 and M)

Are gradually sequestered by G1 CDKs thus allowing activation of later CDKs

52
Q

What regulates teh expression of CDKN2 or INK4s?

A

Expression stimulated by TGFβ

53
Q

What is the role of INK4s / CDKN2?

A

Specifically inhibit G1 CDKs (e.g. CDK4 the kinase activated by growth factors)

54
Q

Outline how growth factors induce cyclin expression

A
  1. Cells enter the cell cycle and receive growth factors in
    response to mitogen
  2. The growth factor will bind to the growth factor receptor
    on the cell membrane to activate signal transducers
  3. The signal transducers activates a cascade of reactions
    resulting in the formation of a perfect nucleus
  4. The nucleus undergoes waves of transcription factor
    activation to express RNA to encode genes and
    proteins
55
Q

How are CDKs activated for expression?

A

G1 CDKs are activated in response to environmental signals, late CDKs by preceding kinase activities.

56
Q

How does RB phosphorylation regulate cell cycle?

A

G1 CDKs hypophosphorylate RB

Late G1/S CDKs hyperphosphorylate RB releasing E2F

Hyperphosphorylated RB is dephosphorylated by protein phosphatase 1

57
Q

What is the result of growth factor signalling?

A

Growth factor signalling activates early gene expression (transcription factors – FOS, JUN, MYC)

58
Q

What is activated by the early gene products induced by growth factors?

A

Early gene products stimulate delayed gene expression (includes Cyclin D, CDK2/4 and E2F transcription factors)

59
Q

How is E2F sequestered?

A

E2F sequestered by binding to unphosphorylated retinoblastoma protein (RB)

60
Q

How does E2F release fluctuate during the cell cycle?

A

G1 cyclin-CDK complexes hypophosphorylate RB and then G1/S cyclin-CDK complexes hyperphosphorylate RB releasing E2F

61
Q

What is the role of E2F?

A

E2F stimulates expression of more Cyclin E and S-phase proteins (e.g. DNA polymerase, thymidine kinase, Proliferating Cell Nuclear Antigen etc.)

62
Q

How are S-phase and G2/M phase cyclin-CDK complexes readily available?

A

S-phase cyclin-CDK and G2/M cyclin-CDK complexes build up in inactive forms

63
Q

How are S/G2/M phase Cyclin-CDK complexes activated?

A

These switches are activated by post-translational modification or removal of inhibitors, driving the cell through S-phase and mitosis.

64
Q

When is DNA damage in the cell cycle detected?

A

DNA damage detected at pre S-phase

Pre M-phase and G2 doublechecks for DNA Damage

65
Q

Outline the result of DNA damage detection at a checkpoint

A

DNA damage detected at checkpoints triggers cell cycle arrest or apoptosis as cells will inhibit cyclin because DNA damage will activate protein kinases

66
Q

How does DNA damage occur?

A

DNA strand is introduced to a mutagen causing a strand break or base pair mismatch

67
Q

How is DNA damage detected at the checkpoints?

A

Mutation is detected by kinases (ATM, ATR) which activates CHEK2 and P53 TF

68
Q

What is the normal outcome of P53 TF?

A

P53 TF causes expression of TP53 in cells but it is normally non-functional as it is quickly degraded by the proteasome

69
Q

How is P53 TF activity altered due to mutation and DNA damage?

A

DNA damage causes kinase (CHEK2) activation, which phosphorylates TP53 inhibiting its degradation

70
Q

What is the consequence of activated TP53?

A

Activated TP53 will bind to TF promoters required for DNA repair

If the DNA damage cannot be prepared, P53 triggers apoptosis to remove mutated cells

71
Q

What enables gene expression to occur?

A

Growth factors binding to receptors induce gene expression

72
Q

How is RB phosphorylated?

A

G1 and G1/S Cyclin-CDK complexes phosphorylate RB in the absence of inhibition by CKIs (expression of these is regulated by TP53 or TGFβ)

73
Q

What does E2F release cause?

A

E2F released, stimulating expression of genes required for S-phase

74
Q

What enables DNA replication to occur during the cell cycle?

A

Cell replicates DNA (expression of S-phase Cyclin-CDK complexes)

75
Q

What are the requirements for a cell to enter mitosis?

A

If all DNA replicated, G2/M Cyclin-CDK complexes cause cell to enter mitosis

76
Q

When do cells exit mitosis?

A

If chromosomes aligned on spindle, exit from mitosis is triggered

77
Q

What is the consequence of failed cell cycle?

A

If process fails, TP53 initiates apoptosis

78
Q

Differentiated cells =

A

post-mitotic
-not G0, but terminally differentiated

Cell type-specific gene expression program
Changed cell morphology + function

79
Q

Cell growth + differentiation intracellular + extracellular signals converge on ……..

A

promoters of key genes

Promoters integrate all the growth factors + inhibitory factors = promoters are “co-incidence detectors”

When promoter receives the right combination of signals, it makes a binary decision on whether to express gene (yes/no) and also decides amount made

CellularPathologyCOPY-aimen n-use this (13 decks)

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