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Cell biology > Exam 4: Cancer 2 > Flashcards

Exam 4: Cancer 2 Flashcards

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1
Q

cancer critical genes

A

genes whose alterations frequently contribute to cancer formation

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2
Q

2 classes of cancer critical genes?

A
  1. oncogenes
  2. tumor suppressor genes
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3
Q

Oncogenes

A

normally promote cell proliferation which help to control the cell cycle
- include gain of function

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4
Q

Gain of function (result)

A

mutation into an overactive form lead to cancer in oncogenes ⇒ heterozygosity

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5
Q

what are dominant effects of oncogenes?

A

(overactivity mutation) 1 mutation takes over fxn
- Normal forms ⇒ proto-oncogenes
- Mutated forms ⇒ oncogenes

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6
Q

Tumor suppressor genes

A

normally suppress cell proliferation
- have a loss of function mutation

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7
Q

Loss of function

A

mutation that leads to cancer in tumor suppressor genes (2 in same gene) forming non functioning proteins
- These mutations are generally recessive

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8
Q

recessive

A

effects are seen when both copies are mutated

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9
Q

how can conversions to proto-oncogenes occur? (4)

A
  1. Deletion or point mutation
  2. Regulatory mutation
  3. Gene amplification
  4. Chromosome rearrangement
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10
Q

Deletion or point mutation activity

A

hyperactive protein made in normal amounts

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11
Q

Regulatory mutation activity

A

normal protein greatly overproduced

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12
Q

Gene amplification activity

A

normal protein greatly overproduced

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13
Q

Chromosome rearrangement

A

nearby regulatory DNA sequence causes normal protein to be overproduced or fusion to actively transcribed gene produces hyperactive fusion protein

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14
Q

what mutation usually occurs with Epidermal growth factor (EGF) receptor?

A

usually is an RTK activated by binding of a growth factor but results in a constitutively active form when mutated

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15
Q

when is the RTK active with a mutation?

A

Active in the absence of the ligand ⇒ ligand usually binds and dimerizes the RTK’s to cross phosphorylation and activate the intracellular domain
- When normally active it makes the signal decrease but when mutated the ligand binding domain is mutated so that it is not there but it has some affinity to form a dimer still

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16
Q

Truncated receptor

A

triggers intracellular signaling in the absence of growth factor

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17
Q

Fusion Abl

A

tyrosine kinase that stimulates overproduction of hemopoietic precursor cells when hyperactive ⇒ turns on cell division signaling all the time

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18
Q

what causes chronic myelogenous leukemia (CML)

A

Breakpoint of the philadelphia chromosome
- a portion of 9 and a portion of 22 which creates a fusion of 2 genes as well as in frame in the protein coding sequences
- This means you get fusion proteins and each part is coming from different original chromosome
- hyperactive version of Abl called Bcr-Abl

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19
Q

Burkitt’s lymphoma

A

cancer of lymphocytes caused by the breakpoint of the chromosome 8 and 14 rearrangement
- Results in abnormal activation of the Myc gene under the control of B lymphocyte regulatory sequences
- one protein is from 14 called immunoglobulin gene enhancer and the other from chromosome 8 has Myc

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20
Q

what is special about the enhancer in Burkitt’s Lymphoma?

A

The enhancer (chromosome 14) is upstream of Myc so the protein coding sequence is normal but the promoter is much stronger
- This occurs in the lymphocyte cells which drives expression of Myc to cause cell division

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21
Q

can we identify oncogenes? How?

A

Yes by dominant transforming effects
- Tumor cells ⇒ isolate DNA ⇒ fragments ⇒ transfect into normal cells ⇒ isolate DNA from the transformed cells ⇒ identify a mutation (oncogene) ⇒ multilayer of transformed cells

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22
Q

what was the first oncogene identified?

A

Ras
- find a plasmid DNA mutation with an abnormal sequence => cells still have normal proto-oncogenes and have 2 good copies but the plasmid they uptook has the dominant effect

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23
Q

can we use the same method for tumor suppressor cells as oncogenes?

A

No because it is recessive and needs 2 mutations
- Only works when you lose the function of both proteins but adding broken proteins won’t do anything

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24
Q

Ras

A

monomeric GTPase, upstream of the MAP kinase cascade
- Ras oncogene has point mutations which make a hyperactive protein (Mutated in 30% of all human cancers)

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25
Q

Retinoblastoma

A

a rare type of cancer caused by loss of Rb gene

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26
Q

2 forms of retinoblastoma

A
  1. Hereditary (both eyes) form
  2. Non hereditary (one eye) form
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27
Q

what is the hereditary form of retinoblastoma?

A

descends from parents to children as a mutation
- Most patients with inherited mutations develop tumors
- Both eyes are affected
- Heterozygote because it is a dominant disorder due to likelihood of mutation

28
Q

non hereditary form of retinoblastoma?

A

extremely rare and only 1 eye is affected because it stems from 1 cell, not in the entire genome of the individual when passed down

29
Q

how many divisions do neural precursor cells do? How does this affect non hereditary RB?

A

10^7 cell divisions in eyes
- about 10^7 x 10^-6 = 10 Rb mutations
- you need to lose both functioning copies and approximately 10 cells with a homozygous mutation will occur => not very likely but would only happen in 1 eye as a result instead of 2
- if you have already inherited a recessive copy, then often both eyes will be effected but not as likely when you don’t have pre-existing mutations
Note: loss of heterozygosity when the second mutation in the same line occurs

30
Q

what do some patients with hereditary retinoblastoma have?

A

a visibly detectable chromosomal defect ⇒ deletion of a specific band on chromosome 13
- The responsible gene cloned was named Rb

31
Q

what does the Rb protein do?

A

Encodes a cell cycle regulator ⇒ brake for entry into s phase
- Involved in many common types of cancers ⇒ lung, breast, etc.

32
Q

how can someone lose their remaining good copy for a tumor suppressor gene?

A

change in DNA sequence
- Genetic or epigenetic
- Aneuploidy, mitotic recombination, gene conversion, deletion, point mutation, epigenetic silencing
- All are genetic mutations except for epigenetic suppression

33
Q

Mutations in oncogenes vs tumor suppressor genes

A
  • in oncogenes ⇒ there are specific positions being affected to make it a hyperactive protein
  • point mutation that create a premature stop codon (thus truncated proteins) occur more frequently in tumor suppressor genes
34
Q

is it more difficult to make a gain of function mutation or a loss of function mutation? What type of mutation is this typically?

A

more difficult to make a gain of function
- usually mutations are a missense mutation

35
Q

Aneuploidy

A

one or more extra or missing chromosomes ⇒ chromosome numbers can be very abnormal sometimes
- different types of cancer can have different forms of aneuploidy
- some tumor types predominantly possess a normal karyotype, while other tumor types display extreme heterogeneity with a dramatic increase in chromosome arm numbers

36
Q

how does lung cancer compare to thyroid cancer as far as abnormal chromosomes?

A

lung cancer has more abnormal chromosomes than something like thyroid cancer

37
Q

what protein disruptions are typical for the cell cycle?

A

Rb ⇒ cell cycle entry

38
Q

what protein disruptions are typical for cell survival?

A

P53 ⇒ tolerance to stress and DNA damage

39
Q

what protein disruptions are typical for cell proliferation?

A

Ras ⇒ signaling cascade that drives cell growth

40
Q

2 signals for proliferation?

A
  1. Signaling that drives cell division ⇒ mitogens
  2. Signaling that drives cell growth ⇒ growth factors
41
Q

what does uncontrolled proliferation of cancer cells require?

A

loss of restrain on proliferation and growth (both are needed)
- you have to go through G1 and the rest of the cell cycle checkpoints which means you need to activate cell division pathways and growth pathways

42
Q

PI 3-kinase/Akt/mTOR pathway is critical for what?

A

cell growth

43
Q

mTOR

A

stimulates protein synthesis, increases glucose uptake and utilization, and increases production of acetyl CoA required for lipid synthesis
- Abnormally activated early in tumor progression
- Explains the excessive rate of glycolysis observed in tumor cells (Warburg effect)

44
Q

how does the mTOR pathway work?

A
  1. a growth factor required for nutrient uptake activates a RTK
  2. this activates PI 3-Kinase
  3. this activates Akt
  4. this activates mTOR to increase protein synthesis
  5. this leads to increased glycolysis, pyruvate citric acid cycle, and eventually lipid synthesis
45
Q

how does p53 and human cancer work?

A

p53 is a tumor suppressor gene and is involved in an extremely wide range of tissues ⇒ involved in DNA damage checkpoint which can activate p53 via phosphorylation events (mutated in 50% of cancers)
- When p53 is stabilized it will not be degraded like usual

46
Q

what roles does p53 play?

A

not essential for normal development, plays important roles when cells are exposed to stressful or harmful conditions ⇒ DNA damage, telomere loss or shortening, osmotic stress, oxidative stress

47
Q

what happens when DNA damage is not that severe?

A

p53 induces cell cycle arrest (p21 expression)

48
Q

what happens when DNA is severe?

A

p53 triggers apoptosis which is relatively harmless of multicellular organisms
- p53 can code cell cycle arrest with p21 genes or senescence or apoptosis if damage is really severe ⇒ apoptosis is harmless compared to cancer

49
Q

what prostate specific expression was specifically monitored in mice with a growing tumor?

A

Luciferen PTEN tumor suppressor gene mutant which is a promoter sequence driving expression of luciferase (enzyme) which generates light

50
Q

what is the process of looking at illuminated tumors in mice?

A

Luciferin (injected) + luciferase ⇒ fluorescence signals reflecting prostate cell descendants (you see the location of the enzyme)
- Follows tumor growth and metastasis in the living organism
- the PTEN mutation causes cancer

51
Q

what mutation patterns do we see with mice in Myc and Ras genes?

A

mice with mutations in only Myc have the lowest death rates, Ras death rates are next, and the rats with combined mutations for both genes have the highest death rates
- all death rates increase with age

52
Q

Synergistic effect

A

mice expressing both Myc and Ras develop cancers earlier and at much higher rate
- Supports the idea that multiple mutations are required for tumorigenesis

53
Q

APC1 gene has extremely high numbers of what type of cancer?

A

colon cancer
Note: this is different from the APC we learned before in the previous chapter

54
Q

Wnt proteins

A

ligands that are evolutionarily conserved family of secreted signaling molecules

55
Q

examples of wnt proteins

A
  1. wingless
  2. int-1
56
Q

wingless protein

A

regulated wing formation and embryonic cuticle in drosophila

57
Q

Int-1

A

promotes breast cancer formation
- Specific viruses tend to hop in the same genetic regions ⇒ viral integration activates Int-1 leading to breast cancer in mice

58
Q

Frizzled proteins

A

7 pass transmembrane proteins that are receptors

59
Q

LDL-receptor related protein (LRP)

A

co-receptor proteins

60
Q

Beta-catenin degradation complex

A

the function of the complex in the picture is to degrade beta catenin ⇒ makes the protein sensitive to phosphorylated Beta-catenin
- Phosphorylated protein is unstable
- axin and APC make the complex stabilized so the kinases can be added in as well as beta catenin

61
Q

what is the pathway without wnt signaling? (4)

A
  1. LRP and Frizzled are on the membrane surface but are not attached to anything
  2. Dishevelled is floating next to the membrane but inactive and not attached to anything
  3. APC, axin, activeGSK3, and active CK1 are all in a complex with a captured 2x phosphorylated Beta-catenin
  4. LEF1/TCF and Groucho are in a complex attached to the wnt target genes which are turned off by this
62
Q

what are the roles of axin and APC proteins in the beta catenin degradation complex?

A

they both act as scaffolding

63
Q

what amino acids do GSK3 and CK1 target?

A

Ser/Thr

64
Q

what does wnt bind to?

A

frizzled and a co-receptor called LRP
- by forming this complex with the ligand and coreceptor it induces phosphorylation of intracellular LRP

65
Q

what happens when LRP is phosphorylated?

A

it sequesters axin which induces the inactivation of degradation complex
- Axin becomes tethered on the membrane so the complex cannot be active and beta-catenin will no longer be phosphorylated

66
Q

what happens when beta-catenin builds up?

A

It builds up in the cytosol and enters the nucleus and induces a target gene expression
- Downstream there are a bunch of wnt target genes including Myc and G1-cyclin to promote cell division

67
Q

what happens if you don’t have APC to stimulate inactivation of beta-catenin

A

then you have a constant triggering of the downstream wnt genes (CycaD, Myc) ⇒ 80% of cancer in this pathway due to APC sensitivity
- mutant APC cannot form the degradation complex
- these genes will be triggered even in the absence of Wnt causing uncontrolled cell division

Cell biology (15 decks)

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