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Cancer Biology > Exam II > Flashcards

Exam II Flashcards

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1
Q

Virus-Induced Cancer

A

Cancer alleles are dominant (20% of cancers)

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2
Q

Non-Virus Induced Cancer

A

Any non-virus source of cancer (80% of cancers)

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3
Q

Retinoblastoma

A

Rare, only 1 in 20,000 children from birth to 6-8 years

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4
Q

Unilateral Retinoblastoma

A

Affects only a single eye; Sporadic form; Mildly elevated risk of other tumors later in life

Requires two “hits” for tumor formation (normal odds are 10^-12/generation for twice); First copy mutated sporadically, second with a LOH Mechanism

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5
Q

Bilateral Retinoblastoma

A

Affects both eyes; Familial form; Great risk of other tumors later in life

Starts with a “hit” so it only takes one mutation for tumor formation

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6
Q

Rb gene

A

Causes retinoblastoma

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7
Q

Loss of Heterozygosity (LOH)

A

Also called “allelic deletion”; a genetic alteration that converts a chromosome region from heterozygous to homozygous

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8
Q

Mechanisms to Loss of Heterozygosity

A

1) Mitotic recombination
2) Gene Conversion
3) Chromosomal Nondisjunction

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9
Q

Mitotic Recombination

A

Recombination occurring during cell proliferation

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10
Q

Gene Conversion

A

DNA polymerase begins replication on template strand, jumps to template strand of homologous chromosome and copies some, jumps back to other template strand and continues copying

More frequent than recombination, so yet more frequent than sporadic

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11
Q

Chromosomal Nondisjunction

A

Heterozygous at Rb locus, nondisjunction, loss of extra chromosome, end up with mutated chromosomes

Much more frequent than sporadic mutation

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12
Q

Chromosomal Localization of the Rb Locus

A

Deletion in 13q12 - 13q14 in retinoblastoma patients.
Chromosome 13, q arm (long arm), region 1, band 3.

A whole lot of exons are missing in the Rb gene in retinoblastoma patients

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13
Q

Rb is the Molecular Governor

A
  • Controls movement from G1 to S at restriction (R) point
  • E2F is required to move from G1 to S (binds to promoter of target genes)
  • Rb controls E2F function
  • Unphosphorylated Rb binds to E2F, preventing transcription of genes necessary for S phase
  • With GF, CDK-cyclin phosphorylates Rb, preventing binding to E2F
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14
Q

DNA Methylation

A
  • Covalently attach a methyl (-CH3) to a cytosine base
  • Mammalian cells only have methylation when C is 5’ to G: MeCpG
  • If MeCpG occurs in or near gene promoter, expression can be repressed
  • DNA Methylation is heritable and reversible
  • Important as mutation in shutting down tumor suppressor genes (P15INK4B inhibits cell cycle and is commonly methylated)
  • The more advanced the cancer, the more methylation
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15
Q

Gene Format

A

5’ UTR - Promoter - Coding (Introns and Exons) - 3’ UTR

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16
Q

Epigenetics

A

The study of heritable changes in gene function that occur without a change in the DNA sequence

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17
Q

DNA Methylation and LOH

A

Work together to shut down tumor suppressor genes; One copy is methylated, and the second is lost through LOH

Frequency: LOH > Methylation > Mutation

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18
Q

Familial Adenomatous Polyposis (FAP)

A
  • Hundreds of thousands of colonic polyps…benign tumors
  • > 95% of colon cancer is due to sporadic mutation; Small number due to inherited genes
  • By 50 yo, need to be examined; 70 yo, >50% have some colonic polyps
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19
Q

Wnt-β-Catenin Pathway

A
  • Without Wnt, GSK-3β phosphorylates β-Catenin, degrading it
  • When Wnt binds to the Frizzled receptor, causes inhibition of GSK-3β via Dishevelled and axin, preventing phosphorylation and degradation of β-Catenin…β-Catenin accumulates, migrates to nucleus, associates with TF, and drives expression of genes
  • This causes colonic polyps
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20
Q

Wnt

A

Mitogenic factor…GROW!

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21
Q

β-Catenin

A

Can drive the cell to proliferate; Almost exclusively responsible for colon cancer

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22
Q

Apc

A
  • Tumor suppressor…brings β-Catenin to GSK-3β (glycogen synthase kinase-3β) for degradation
  • Mutation makes Apc lose ability to bring β-Catenin to GSK-3β for degradation
  • Apc protein has multiple protein binding domains, and the gene encoding Apc is frequently mutated
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23
Q

Axin and Wtx

A

Scaffold for protein complex

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24
Q

Colonic Crypts

A
  • 90% of colon cancer is caused by mutation of APC (-/-) gene
  • 10% Apc is methylated, β-Catenin is mutated and cannot be phosphorylated
  • Normal cells have Wnt signal stem cells…β-Catenin interacts with TF and proliferates stem cells…cells move upwards…Wnt decreases…β-Catenin degraded…Apoptosis in 3-4 days
  • Tumor cells…Apc is defective…β-Catenin levels remain high even without Wnt signaling…cells stop migrating upward, accumulating in crypts…adenomatous polyp
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25
Q

Anti-Growth Genes

A

Gatekeepers and Caretakers

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26
Q

Gatekeepers

A
  • Directly control the biology of cells by affecting how they proliferate, differentiate, or die
  • Tumor suppressor genes are GATEKEEPERS
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27
Q

Caretakers

A

Control the biology of cells through maintenance of cellular genomes

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28
Q

Cell Cycle Clock

A
  • Located in the nucleus
  • A network of interacting proteins (a signal processing circuit) that receives signals from various sources both outside and inside the cells, integrates them, and decides the cell’s fate
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29
Q

Four Phases of Mammalian Cell Cycle

A

(G0)

  • G1 (prepare cell for DNA synthesis…12-15 hr)
  • S (synthesis of DNA…6-8 hr)
  • G2 (prepare cell for DNA separation…3-5 hr)
  • M (mitosis/PMAT…45 min - 1 hr)
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30
Q

Interphase

A

DNA evenly distributed as chromatin in nucleus; Proteins and RNA made here

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31
Q

Prophase

A
  • Chromatin condensed into chromosomes

- Mitotic spindle assembled into centrosomes

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32
Q

Metaphase

A
  • Chromosomes line up along metaphase plate

- Mitotic spindle (tubulin) has attached to centromeres

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33
Q

Anaphase

A

-Chromatid pulled to each side

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34
Q

Telophase

A
  • Chromatid completely separate at poles

- Nuclear membrane begins to reform

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35
Q

Checkpoints in Cell Cycle

A
  • End of G1: DNA damage checkpoint (entrance into S phase blocked if damaged)
  • S phase: DNA damage checkpoint (replication halted if damaged)
  • End of G2: entrance into M phase blocked if DNA isn’t replicated
  • M: anaphase blocked if chromatids are not properly assembled on mitotic spindle
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36
Q

G1 Phase Importance

A
  • The cell only monitors environmental signals in G1
  • After G1, the cell MUST DIVIDE
  • Can respond to GFs and TGF-β for 80-90% of phase
37
Q

Restriction (R) Point

A

The point in time when the cell must make the commitment to advance through the remainder of the cell cycle through the M phase, to remain in G1, or to retreat from the active cell cycle into G0

38
Q

TGF-β

A
  • Transforming growth factor
  • Inhibits cell growth
  • Antagonist to GF
  • Only affects cell in G1 phase, before R point
  • Induces expression of p15 (CDKI for D-CDK4/6)
39
Q

Cyclin

A

The regulatory subunits of the heterodimeric protein kinases that control cell cycle events; Regulates kinase activity of CDK

40
Q

Cyclin-Dependent Kinases (CDKs)

A
  • A group of protein kinases that are involved in the regulation of the cell cycle
  • Serine/Threonine Kinases
41
Q

Cyclin and CDKs

A
  • Association of cyclins with CDKs ACTIVATES CDK kinase activity
  • Cyclin-CDKs complexes constitute the engine of the cell cycle clock…drive cell cycle
42
Q

Pairing of Cyclins with CDKs

A
  • In G1 to R, D-type cyclin with CDK4/6
  • From R in G1 to after beginning of S, E-type with CDK2
  • Beginning of S to middle, A-type with CDK2
  • Middle of S to end of G2, A-type with CDC2
  • M, B-type with CDC2
43
Q

Fluctuation of Cyclins and CDKs

A
  • CDK levels vary minimally
  • Cyclin levels vary dramatically
  • Only D-type cyclins respond to environmental factors…B, E, and A are AUTOMATIC after elevated D-type
  • After the R-point, the cyclin-CDK complexes in one phase of the cell cycle are responsible for activating those in the subsequent phase and for shutting down those that were active in the previous phase
44
Q

CDK Inhibitors (CDKIs)

A
  • A group of proteins that affect the activities of cyclin-CDK complexes
  • 7 important CDKIs in 2 groups: 1) inhibit D-CDK4/6 and 2) inhibit everything else
  • p16/15/18/19 inhibit D-CDK4/6
  • p57/27/21 inhibit E-CDK2, A-CDK2, A-CDC2, B-CDC2
  • These 7 proteins are TUMOR SUPPRESSORS
45
Q

pRb is the Molecular Governor of the R-Point Transition

A
  • pRb can be phosphorylated on 14 sites
  • Phosphorylation of pRb increases dramatically at R point
  • G0…pRb not phosphorylated
  • G1…hypophosphorylated…1 site phosphorylated
  • R point…hyperphosphorylated…at least 12 more phosphorylated (13 or 14 phosphorylated total)
46
Q

pRb Phosphorylation

A
  • D-CDK4/6 complexes drive pRb hypophosphorylation (active form)
  • Levels of cyclin E increase at R point
  • E-CDK2 complexes drive pRb hyperphosphorylation (inactive form)
47
Q

pRb Controlling Transcription Activity of E2Fs

A
  • Hypophosphorylated pRb binds to E2F (TF), blocking transcription-activating domain
  • Hyperphosphorylated pRb releases E2F, allowing E2F to function as TF
  • As cell enters S phase, E2F inactivated and/or degraded
  • pRb and Histone Deacetylase (HDAC…keeps chromatin densely packed) repress transcription
  • Histone Acetylase keeps chromatin in loose state, activating transcription
48
Q

DNA Tumor Virus Oncoproteins Mess with pRb

A

Viral oncoproteins bind to pRb, causing a conformation change in pRb so it releases E2F which is now free to transcribe (same effect as hyperphosphorylation)

49
Q

p53

A

A transcription factor functioning as a tumor suppressor important in multicellular organisms; Critical in conserving stability; Monitors cell for damage…responds to cell damage by activating other proteins…cannot repair means apoptosis

-Mutated in 30-50% of commonly occurring human cancers…gene that is the most frequently mutated

50
Q

Apoptosis

A

A form of programmed cell death in multicellular organisms (cannot stop it once it is started)

51
Q

p53 Mutations

A
  • Most p53 mutations (74%) due to missence point mutation (amino acid substitution), like ras
  • 95% of p53 mutations affect DNA-binding domain so that it is no longer to bind DNA and act as TF
52
Q

Dominant-Interfering/Dominant-Negative Mutation

A

Mutation in one allele of the gene interferes with or obstructs the function of the WT copy of the gene

  • p53 is a homotetramer…the whole things acts as TF
  • p53 only needs ONE “hit”…only one p53 allele must be affected to nearly inactivate it completely
  • p53 +/- (heterozygous) means only 1/16 p53 subunit combinations will work properly
53
Q

p53 Activation

A
  • Short lifespan, about 20 minutes
  • Anything abnormal, p53 triggered…more and more p53 protein…due to post-translational stabilization
  • p53 levels do NOT rise due to increased transcription (mRNA levels remain constant)
54
Q

DNA Damage and p53

A

DNA Damage -> phosphorylation of p53 -> Mdm2 binding site blocked -> inc p53 -> inc p21 -> CDK inhibition -> cell cycle stopped

55
Q

Control of p53 Levels by Mdm2

A
  • mdm2 is a target gene of p53
  • (Normal cells) Elevated p53 induces expression of Mdm2 which binds to p53, exports it to cytoplasm, triggers p53 degradation (negative-feedback loop)
56
Q

p53 Phosphorylation

A

Phosphorylation of p53 AA residues in N-terminal domain blocks Mdm2 binding, saving p53 from degradation

57
Q

ARF

A
  • ARF is a tumor suppressor by preventing p53 degradation
  • Associates with and inactivated Mdm2 in nucleus (cannot bind with p53 now)
  • Increase in inactivated Mdm2 causes increase in p53
  • Eliminates cells with overly active E2F signaling
58
Q

Apoptotic Cells…

A

1) Cell shrinks and membrane becomes fragmented (blebs)
2) Chromatin condenses and nucleus shrinks
3) Genomic DNA fragments
4) Fragmented cells engulfed by macrophages

59
Q

2 Signaling Pathways Trigger Apoptosis

A

1) Mitochondrion-Dependent Pathway

2) Receptor-Activated Apoptotic Pathway

60
Q

Mitochondrion-Dependent Pathway

A
  • Intrinsic apoptotic pathway; Stress-activated apoptotic pathway
  • Bcl-2 Protein Family controls mitochondrion-dependent pathway
61
Q

Receptor-Activated Apoptotic Pathway

A

Extrinsic Apoptotic Pathway; Receptors on cell membrane

62
Q

Bcl-2 Protein Family

A
  • Bcl -> B-cell lymphoma
  • At least 24 genes in this family
  • Over-expressed in B-cell lymphoma, causing cancer
  • The 24 genes can be divided into 1) Bcl-2 family (a sub-family) 2) Bax family 3) BH3-only family
  • BH is a Bcl-2 homology domain
  • Bax family is Bcl-2 minus BH4
  • BH3-only family only contains BH3 domain
  • BH4 must be pro-survival gene then (inhibits apoptosis)
63
Q

Bcl-2 Family

A

(The sub-family)

  • Antagonizes (neutralizes) Bak and Bax
  • Prevents apoptosis when cell is under stress
  • Can be in mitochondria or cytosol
64
Q

Bax Family

A
  • Initiates mitochondrion-dependent pathway
  • Bak located in mitochondrial membrane
  • Bax located in cytosol
  • Bax moves into mitochondrial membrane and creates a channel in the outer-membrane (with the aid of Bak)
  • Apoptotic factors are released from inter-membrane space of mitochondria, initiating apoptosis
65
Q

BH3-Only Family

A
  • In cytosol to monitor conditions

- If triggered, inhibits/neutralizes Bcl-2 family, causing apoptosis

66
Q

Balance Between Pro- and Anti- Apoptotic Proteins

A

Need a balance, no absolute amount, just the ratio of anti-apoptotic to pro…determines susceptibility of cells to apoptotic stimuli

67
Q

Cytochrome C

A
  • Cytochrome c plays critical role in apoptosis
  • Used in ETC in intermitochondrial space
  • Once in cytosol, triggers apoptosis
  • Bak/Bax cause release of cytochrome c
  • In cytosol, cytochrome c assembles with Apaf-1
  • Once cytochrome c is released, it is all over
68
Q

Apoptosome

A
  • The wheel of death
  • Assembly of 7-spoked wheel where Apaf-1 is spokes and cytochrome c molecules form tips of spokes
  • Once wheel forms, starts spinning…converts pro-caspase 9 into…active caspase 9…functions to convert pro-caspase 3,6,7 to active forms
69
Q

Apoptotic Caspase Cascade

A

Death signals…activation of Bax and Bak…Disruption of mitochondrial membrane…Release of cytochrome c & Smac/DIABLO…assembly of apoptosome & liberation of caspases from IAP inhibition…activation of pro-caspase 9…activation of pro-caspace 3,6,7…cleavage of death substrates…cell death

  • IAPs (inhibitors of apoptosis) inhibit caspases 3,6,7
  • Smac and DIABLO released with cytochrome c from mitochondria to inhibit IAPs
70
Q

Cleavage of Death Substrates

A

Executioner caspases 3,6,7 cleave…

  • Lamin (supports nuclear membrane…nucleus shrinks once lamin is cleaved)
  • Inhibitor of DNase (ICAD)…frees up DNase, allowing fragmentation of chromosomal DNA
  • Cytoskeletal proteins…cell shrinks and forms blebs
71
Q

Death Receptors

A
  • About 30 death receptors in human genome
  • Form a trimer and become activated
  • Cytoplasmic tails act via the FAS-associated death domain (FADD) protein to assemble a death-inducing signaling complex (DISC)
  • DISC activates pro-caspases 8 and 10
  • Caspases 8 & 10 activate pro-caspases 3,6,7
72
Q

Activation of Apoptosis by p53

A

1) p53 induces expression of Fas receptor, sensitizing the cell to Fas ligands (Fas is a death ligand)
2) p53 induces expression of IGF-binding protein-3 (IGFBP-3) which sequesters IGF-1 and IGF-2 (pro-survival, anti-apoptotic ligands)…IGFBP-3 neutralizes IGF 1/2…binds IGFR
3) p53 induces expression of Bax
4) p53 induces expression of foxo3 (foxo3 is a TF, responds to oxidative damage, a pro-apoptotic protein)

73
Q

Cell Immortality

A
  • The ability to proliferate indefinitely
  • Most cells divide only a limited number of times before entering senescence
  • Tumor cells must turn off this mechanism to form life-threatening tumors
  • ESCs have the ability to proliferate indefinitely
  • Tumor cells resemble ESCs in proliferation
74
Q

Senescent Cells

A
  • Viable, differentiated cells that lose the ability to divide
  • Human cells can usually divide 50-60 times
75
Q

Cell Lineage

A

A pedigree of cells related through mitotic division

76
Q

Theoretical Growth of Tumor

A
  • If tumor cells perfectly divided and survived, it would only take 40 doublings and 10^12 tumor cells
  • Substantial difficulty in dividing in reality
  • High rate of attrition leads to loss of many cells in each cell generation
77
Q

Cell Generation Clock

A
  • Measures the cumulative physiological stress and the allowed quota of divisions for a cell
  • Measures cumulative physiological stress (molecular damage)…once the damage exceeds a threshold, the cell enters senescence (high levels of CDKIs)
  • Measures how much allowed quota has been used…once quota is used up, cell enters state of crisis, leading to apoptosis
78
Q

Senescence Circumvention

A
  • Must inactivate p53 and Rb
  • Important barrier to overcome for cancer formation
  • LT (Large T) can inactivate both p53 and Rb
79
Q

Telomeres

A
  • Located at ends of chromosomes
  • Composed of 5’-TTAGGG sequence, repeated thousands of times (5-10 kb)
  • Complexes of telomeric DNA and telomere-binding proteins are the “telomere”
  • Telomeres prevent end-to-end fusion of chromosomal DNA
  • Telomere length registers CELL GENERATIONS
80
Q

TRF2

A
  • TRF2 is key protein in maintaining normal telomere structure
  • Inactivation of TRF2 causes MASSIVE fusion of chromosomes
81
Q

Shortening of Telomeres

A
  • Telomeres shorten 50 to 100 base pairs per cell generation
  • Once telomere length reaches about 3 kb, cell goes into crisis
  • Vast majority if cells will begin dying now, BUT 1 or 2 may survive
82
Q

Structure of Telomeres

A
  • 5 to 10 kb of tandem repeats of TTAGGG
  • G-rich strand of telomeric DNA extends beyond the C-rich strand, resulting in a 3’ overhang that is often several hundred nucleotides long
83
Q

Telomerase

A
  • An enzyme that adds specific DNA sequence repeats (TTAGGG) to the 3’ end of DNA strands in the telomere regions
  • Present early in embryogenesis and is largely lost during differentiation
  • Telomerase activity is not detectable in normal human somatic cells, but is detectable in 85-90% of human tumor cells
  • Of 10 proteins, two make up the core of the telomerase holoenzyme, 1) hTERT (human telomerase reverse transcriptase) and 2) hTR (telomerase-associated RNA)
84
Q

Telomerase Holoenzyme

A
  • hTR binds to the existing telomere (G-strand)

- hTERT adds nucleotides

85
Q

hTERT

A

hTERT expression determines telomerase activity because hTR RNA levels have little fluctuation

86
Q

Alternative Lengthening of Telomeres (ALT)

A

-10-15% of cancers use ALT, not telomerase

87
Q

Tumorigenesis

A
  • Production of a new tumor/tumors
  • Driven by a sequence of randomly occurring mutations and epigenetic alterations of DNA that affect the genes controlling cell proliferation, survival, and other traits associated with the malignant cell phenotype
88
Q

Normal Cancer Development Takes Many Years, even Decades

A
  • Cancer takes a long time to develop…
    1) Cancer becomes more incident starting around 50 yo and increases from there until 85 years old
  • Takes about 35 years for smoking to cause cancer
  • Cumulative exposure to a carcinogen, rather than age at exposure, determines likelihood of developing cancer
    2) Normal -> Hyper/Meta Plastic -> Dysplastic [Benign] -> [Malignant] Neoplastic/Locally Invasive -> Metastatic
    3) Colon Tumor progression and LOH in chromosomal arms
89
Q

Clonal Succession

A

A mutant cell spawns a large flock of descendants and among those numerous descendants, a new mutational event will trigger yet another wave of clonal expansion

Cancer Biology (3 decks)

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