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HDT 3.2 > Cell Proliferation/apoptosis > Flashcards

Cell Proliferation/apoptosis Flashcards

1
Q

describe how cell proliferation occurs?

A
  1. growth factors bind to their cytokine receptors
    e.g. EGF/ PDGF
  2. activated intracellular signalling
  3. change in gene transcription
    e.g. up/down-regulation of gene transcription
  4. knock-on effects on DNA replication, cell cycle, mitosis etc.
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2
Q

how can cell proliferation drive cancer progression?

A

down-regulation of cytokine signalling to initiate/stop gene transcription

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3
Q

what are proto-oncogenes?

A

normal genes that control proliferation/growth that can become oncogenes due to mutations/increased expression

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4
Q

what are some examples of oncogenes/tumour-inducing agents?

A
  1. Gene amplification/over expression: HER2 in breast cancer
  2. Translocations resulting in hybrid oncogene: BCR-ABL in leukemia
  3. Missense mutations resulting in constitutively active protein: EGFR in lung cancer, B- RAF in melanoma
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5
Q

describe tumour cells compared to normal cells, in terms of genes.

A

increase no. of proto-oncogenes
increase gene transcribed
increase gene expression

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6
Q

what receptors do growth factors bind to?

A

mainly tyrosine kinase receptors
Tyr R

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7
Q

describe Tyr R ?

A

dimer receptor

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8
Q

what happens when growth factors bind to the Tyr R ?

A

becomes phosphorylated
causes…
- conformational change
- dimerisation
- activation of tyrosine kinase activity

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9
Q

how can additional receptors bind to Tyr R?

A

Tyr R is activated and phosphorylated
phosphorylated residues allow various cytoplasmic receptors to join

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10
Q

what are some examples of Tyr R?

A

PGDF receptor
EGF receptor
Insulin
IGF receptor (insulin-like GF)

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11
Q

what are some examples of growth factors?

A

platelet-derived growth factors
epidermal growth factors
insulin
insulin-like growth factors
transforming growth factors (TGF-a and TGF-b)

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12
Q

what are some examples of receptors that bind to Tyr R?

A

RAS pathway
serine/threonine kinase cascades
P.I./lipid signalling pathway
other tyrosine kinases
phospholipase Cy

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13
Q

which receptors that bind to Tyr R drive gene proliferation?

A

RAS pathway
serine/threonine kinase cascades
other tyrosine kinases

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14
Q

what happens to Tyr R in cancerous tumour?

A
  1. amino acid changes/partial deletion
    = change tyr activity
    = loss of ‘receptor domain’
    = GF independent signalling
  2. gene amplification/over-expression
    - increased expression of normal receptors
    - overexpression of aberrant receptors
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15
Q

what is HER2?

A

an epidermal growth factor receptor (EGFR)
amplifaction/duplication of HER2 gene in breast cancer

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16
Q

what is BCR-ABL?

A

a fusion kinase = BCR- ABL increases cell proliferation

  1. BCR = promotes cell survival
    - tyr kinase
    - GTP regulator
  2. ABL = promotes cell survival
    - cytoplasmic Tyr Kinase
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17
Q

what happens when BCR and ABL genes fuse?

A

BCR loses GTP regulation
ABL loses inhibitory domain which inactivates ABL

= INCREASES BLOOD CELL PROLIFERATION = leukemia

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18
Q

what genes are apart of the RAS family?

A

h-ras
k-ras
n-ras

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19
Q

why is the RAS family important?

A

Most commonly mutated oncogene

20
Q

what is a common oncogenic mutation in the RAS cycle?

A

reduced GTPase-activating proteins = no inactivation of RAS = increased cell proliferation due to constant RAS signalling

21
Q

what does activated RAS do?

A

phosphorylated MEK which phosphorylates ERK = phosphorylates to activated transcription factors

22
Q

where is B-RAF mutations common?

A

melanoma (80%)
lung
colorectal cancers

23
Q

where do B-RAF mutations occur?

A

RAS cycle

24
Q

what is cell apoptosis?

A

programmed cell death,
allows elimination of damaged cells

25
Q

what mediates cell apoptosis? and how?

A

caspases (caspase-9 into caspase-7 & caspase-3) by cleaving cellular proteins and indirectly cellular DNA

26
Q

describe cell apoptosis method

A
  1. Condensation of nuclei and fragmentation of chromosomal DNA
  2. Condensation and fragmentation of cytoplasm
  3. Release of mitochondrial cytochrome C
  4. Membrane blebbing
  5. Phagocytic clearance
27
Q

how is apoptosis controlled?

A

in healthy cells - BCL2 represses apoptosis

apoptotic stimuli inhibit BCL2

28
Q

what are apoptotic stimuli?

A

pro-apoptotic receptor
cellular stress (DNA damage, loss of growth factors, anoxia, infection and oxidative stress)

29
Q

what is p53?

A

transcriptional factor responds to DNA damage
1. promotes apoptosis if damages are not reparable via activation of pro-apoptotic genes
2. suppresses anti-apoptotic factors

30
Q

what are the 4 main outcomes of an activated p53?

A
  1. angiogenesis
  2. growth arrest
  3. DNA repair
  4. apoptosis
31
Q

what are some treatments relating p53?

A

chemotherapy that induces larger levels of DNA damage to induce p53- dependent apoptosis

32
Q

whats MDM2?

A

negative regulator of p53
degrades p53
negative feedback

33
Q

what happens if MDM2 is overexpressed?

A

loss of p53 activity due to larger degradation

34
Q

where is cytochrome C released from?

A

mitochondria via BAX/BAK pro-apoptotic genes

35
Q

what do caspase 3 and caspase 6 do?

A

DNA fragmentation and protein cleavage

36
Q

why is cytochrome c released ?

A

detects levels of intrinsic stress

37
Q

what does BCL-2 do?

A

repress cellular apoptosis by suppressing BAX/BAK = inhibit cytochrome C release

37
Q

what is the expression of BCL-2 in cancerous cells?

A

over expressed

38
Q

How do we target treatments to control proliferation/cell death?

A
  1. target RTKs
  2. target BCL-2/BCL-XL
39
Q

how do we targets RTK?

A
  1. target antibodies to receptor
    - inhibit ligand binding
    - inhibit dimerisation
    - induce cell killing of tumour cells
    - inhibit phosphorylation
  2. small molecules inhibit RTK (intracellulary)
40
Q

what antibodies target RTKs?

A
  1. trastuzumab (HERCEPTIN)
    - blocks internalisation
    - partial block of downstream signalling
    - promotes antibody-dependent cytotoxicity = kills tumour cells
  2. pertuzumab
    - blocks dimerisation and activation
    - effective when HER2 is activated not overexpressed
  3. cetuxumab
    - blocks EGF binding
  4. panitumumab
    - blocks EGF binding
41
Q

what are HER2 targeted treatment?

A

trastuzumab - mAb
pertuzumab - mAb
lapatinib - small molecule

for breast cancer

42
Q

what are EGFR targeted treatment?

A

cetuximab - colorectal cancer
panitumumab - colorectal cancer
erlotinib - lung cancer

43
Q

what is erlotinib?

A

reversible ATP competitor (small molecules) IN EGFR inihibitor

resistance can occur EGFR

44
Q

what are BCR-ABL inhibitors?

A

IMATINIB drug - some ppl experience resistance and relapse

used in CML - Chronic myelogenous leukemia

45
Q

MOA of BCR-ABL inhibitors?

A

competitively inhibit of ATP binding to active site = inhibit TYR K

HDT 3.2 (17 decks)

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