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EXMD504 > 3. Oncogenes and Tumor Suppressors > Flashcards

3. Oncogenes and Tumor Suppressors Flashcards

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1
Q

4 characteristics of neoplasia

A
  1. dysregulated cellular differentiation
  2. irreversible aberrant proliferation and size
  3. IMMORTAL –> can proliferate but not differentiate
  4. selective growth advantage
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2
Q

what is a selective growth advantage?

A

more cells produced than die

(ratio btwn birth and death of cells >1)

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3
Q

what is dysplasia?

A

pre-neoplastic tissue with abnormal properties (size, shape) and irregular dividing

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4
Q

how does the placenta compare to cancer?

A

placenta has same hallmarks as cancer but can even grow faster!!

most work studying angiogenesis in cancer uses placenta

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5
Q

what did researchers find in 1902 about cancer? why?

A

that cancer is genetic disease –> some chromosomes stimulate cell division while others inhibit it

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6
Q

what did researchers find in 1911 about cancer?

A

chicken grew spontaneous sarcoma –> ground up sarcoma and injected into young chickens –> sarcoma grew again

therefore this cell-free extract is oncogenic

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7
Q

what did Huebner and Todaro do in 1969?

A

made the word ONCOGENE

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8
Q

what did Martin do in 1970?

A

found that v-src drives sarcoma

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9
Q

what did President Nixon do in 1971?

A

declared war on cancer via National Cancer Act –> allowed for high-level funding of cancer

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10
Q

what did Stehelin, Bishop, Varmus find in 1976?

A

found v-src in un-infected cells so oncogenes must be in our genome as proto-oncogene then become activated and cancerous

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11
Q

what is oncogene?

A

gene that increases selective growth advantage of cancer in a cell

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12
Q

what is proto-oncogene?

A

normal gene that can become oncogene due to mutations or increased expression

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13
Q

what is tumour suppressor?

A

gene that increases selective growth advantage of cancer when INACTIVATED by mutation

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14
Q

what is amplification mutation?

A

making many copies

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14
Q

what is rearrangement mutation?

A

mutation that juxtaposes nucleotides that are normally separated

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14
Q

what are the 4 types of mutations that drive cancer?

A
  1. amplification
  2. Indel
  3. rearrangement
  4. SBS
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14
Q

what is indel mutation?

A

small insertion or deletion of a few nucleotides

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15
Q

what is SBS mutation?

A

single-nucleotide substitution

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16
Q

what is a driver gene mutation?

A

directly/indirectly gives selective growth advantage to cell

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17
Q

what is a passenger mutation?

A

mutation with no effect on selective growth advantage of cell –> accidental

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18
Q

do all cancers have the same number and types of mutations?

A

no, diff cancers have diff numbers and types of mutations

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19
Q

what gene follows a loss of heterozygosity model?

A

Rb1 tumour suppressor

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20
Q

describe the loss of heterozygosity model and the 2 types

A

gene must be “hit” on both alleles

SOMATIC: 2 somatic mutations = cancer

GERMLINE: 1 inherited germline mutation + 1 somatic mutation = cancer

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21
Q

why do both alleles need to be lost in loss of heterozygosity model?

A

if only 1 allele, the remaining allele will compensate and not get cancer –> only become predisposed to cancer

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22
which 2 genes follow the haploinsufficiency model?
p53 and PTEN
23
what is the haploinsufficiency model?
a small loss of gene/1 allele lost = CANCER!
24
does haploinsufficiency model need to be germline or somatic mutation?
doesn't matter
25
describe haploinsufficiency model for P53?
small loss of gene/1 allele missing = CANCER!
26
describe haploinsufficiency model for PTEN
it has OBLIGATE haploinsufficiency - some loss of gene = CANCER - total loss of gene is bad for cancer bc cell's defense mechanisms will be more efficient
27
where do oncogenes work in the cell?
anywhere that gives them a selective growth advantage
28
what is RAS?
GTPase proto-oncogene that is highly mutated to be more in the GTP/active state to promote cancer
29
how is RAS inactivated?
NF1 tumour suppressor to make RasGDP
30
how is RAS activated?
SOS1 oncogene to make RasGTP
31
describe RAS signaling normally
normally cells proliferate by growth factors 1. growth factors bind to receptor tyrosine kinase 2. tyrosine gets phosphorylated to activate receptor 3. RAS can activate proliferation, survival, etc.
32
describe RAS signaling in cancer cells
doesn't require growth factors bc RAS mutated to be in active state
33
are there more tumour suppressors or oncogenes?
ONCOGENES
34
What are the 2 domains of p53 and the function of each?
1. DNA binding domain --> bind target genes 2. oligomerization domain --> so it can become an active tetramer
35
what did p53 evolve from?
p63/p73 ancestor gene
36
what determines whether p53 induces apoptosis or survival?
type and intensity of signal
37
what happens when there is basal p53?
for cell maintenance, mitochondrial function, etc.
38
what happens when there is LOW stress and DNA damage?
TRANSIENT arrest, repair and autophagy --> cell recovers and survives
39
what happens when there is HIGH stress and DNA damage?
senescence, apoptosis, necrosis --> cell death
40
is p53 always present in human tumours? how?
always present, just mutated or inactivated so it cannot function properly
41
what are the 3 types of p53 mutations?
1. gain of function 2. dominant negative 3. loss of function
42
what happens with a gain of function mutation of mutant p53?
MUTANT p53 is active to allow cell proliferation, survival, and metastasis
43
what happens with a dominant negative mutation of mutant p53?
blocks WT p53 from binding to prevent tetramer formation
44
what happens with a loss of function mutation of mutant p53?
mutant p53 is inactivated, allowing apoptosis/DNA repair/growth suppression
45
what is the highest risk factor for getting cancer?
age
46
why is age the highest risk factor for getting cancer?
multiple oncogenic events build up throughout life to develop cancer --> 1 is not enough
47
describe the demonstration of oncogene collaboration using 2 types of fibroblasts (4 steps) and what this showed us
1. looked at immortal fibroblasts and normal embryo fibroblasts 2. add tumour DNA to immortalized cells --> cells were transformed and became malignant 3. add Myc/Ras alone to normal fibroblasts --> cells were not transformed, no cancer 4. add Myc/Ras together to normal fibroblasts --> cells were transformed and became malignant shows that minimally need activation of 2 oncogenes
48
what is the role of Myc?
signals cells to enter the cell cycle and prolfierate
49
what happens when you have fibroblast with Myc and serum?
proliferation and survival --> survival bc serum has growth factors
50
what happens when you have fibroblast with Myc and no serum?
proliferation, then apoptosis
51
what happens when you have fibroblast with Myc and Ras?
proliferation and apoptosis is blocked, survival!! even in absence of growth factors
52
based on above experiments, describe oncogene collaboration between Myc and Ras?
Myc induces proliferation and Ras inhibits apoptosis --> cells can grow without dying
53
what happens when oncogenes are activated?
tumour suppressors are also activated to counteract oncogenes
54
what tumour suppressor do Myc and Ras activate? what does this lead to?
Activate ARF --> blocks MDM to stabilize p53, allowing apoptosis
55
what is ARF?
from alternate reading frame of INK4a locus that encodes p16
56
what is senescence?
"to grow old" state of irreversible growth arrest --> never re-enters cell cycle and deteriorates with age
57
how does senescence prevent cancer?
prevents excessive/aberrant cell proliferation
58
what 3 things trigger senescence?
1. telomere shortening 2. reduced ARF locus 3. DNA damage
59
do you want to prevent or induce senescence to prevent aging?
PREVENT bc senescent cells are what make you look old
60
do you want to prevent or induce senescence to prevent cancer?
INDUCE
61
how does Ras induce senescence?
Ras activates ARF which blocks MDM2 to stabilize p53 --> senescence
62
what is the Hayflick limit?
replicating limit --> number of times a cell population will divide until cell division stops
63
are all tumour cells senescent?
most are, but a few escape and cause carcinoma
64
what is oncogene addiction?
when oncogenes drive cancer, cell becomes addicted and critically dependent on the oncogene
65
how can we use oncogene addiction to find targeted therapy?
inhibit this specific function = cell death
66
3 models for oncogene addiction
1. genetic streamlining 2. oncogenic shock 3. synthetic lethal
67
what is genetic streamlining?
cells streamline 1 pathway and inhibit other pathways --> if the remaining pathway is inhibited, cell dies
68
what is oncogenic shock?
pro-survival pathway dominates pro-apoptosis pathway but blocking this = apoptosis
69
what is synthetic lethal?
loss of 1 pathway allows for survival but loss of both = apoptosis
70
what is an example of targeted therapy?
kinase inhibitors
71
what are kinase inhibitors used for? how do they work?
To treat chronic myeloid leukemia with Philadelphia chromosome mutation --> selectively kills cancer cells
72
what are the 2 ways to develop resistance to targeted therapy?
1. vertical resistance 2. horizontal resistance
73
what is vertical resistance?
cells activate something downstream in pathway being blocked
74
what is horizontal resistance?
drug works on intended pathways but cell activates alternate pathway that is not targeted
75
what is the challenge with treating cancer?
cancer is big and heterogenous --> even if you know initiating mutation, there are many clones and oncogene addictions
76
since a tumour is heterogenous, can you use many drugs to target the different parts?
can lead to many side effects

EXMD504 (12 decks)

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