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6.10 caner genes Flashcards

1
Q

oncogene activation by normal expression of a protein with altered function

A

ras, abl

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2
Q

oncogene activation by overexpression of a normal protein

A

myc

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3
Q

overexpression can come from

A

amplification, translocation next to active promoter, insertion of viral promoter

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4
Q

Chronic myelogenous leukemia translocation

A

translocation of abl gene from chromosome 9 to chormosome 22, sitting right next to the BCR locus –> under this promoter the tyrosine kinase encoded by abl is overexpressed –> chronic myelogenous leukemia

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5
Q

gleevec

A

specific tyrosine kinase inhibitor that is encoded by abl, since specific to the cancer cells no side effects

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6
Q

burkitts lymphoma mutation

A

translocation of myc gene from chromosome 8 to chromosome 14, sidding beside the Ig gene

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7
Q

amplifcation of N-myc

A

n-myc produces double minutes, and amplification can turn cover a large region of the chromosome that can be morphologically picked up

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8
Q

what can you add for membranes to fuse together

A

propylene glycol - used to fuse immortal cell and specific bcell to make monoclonal antibody

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9
Q

what phenotype do normal and malignant fused cells give you

A

normal phenotype - something on the normal chromosome suppresses the malignant phenotype bc if that chromosome is kicked out you’ll see the malignant phenotype

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10
Q

Retinoblastoma inherited form

A

multiple, deletions in all cells

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11
Q

Retinoblastoma spontaneous form

A

single, deletions only in tumor

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12
Q

Rb inheritance

A

one allele inactivated at birth, 2nd inactivated by somatic event

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13
Q

Rb function

A

phosphorylation regulates activity –turns it off, when unphosphorylated the Active Rb gene sequester factors necessary for entering the cell cycle – tumor suppressors

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14
Q

Viral proteins and Rb

A

viral proteins interfere with Rb gene

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15
Q

hypophosphorylated Rb

A

binds E2F transcription factors, and that complex binds DNA preventing transcription

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16
Q

Rb is released from E2F when

A

CDK4 and 6 hyperphosphorylate Rb, releasing E2F, allowing several genes to be transcribed

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17
Q

If Rb is absent or not functional

A

all the genes normally inhibited by E2F will be constitutively expressed

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18
Q

E2F/DP1/Rb complex inhibits transcription by

A

recruiting histone deacetylase, that makes chromatin more compact — when the complex is released, histone deacetylase is released allowing for the transcription of genes

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19
Q

Rb can by phosphorylated by

A

CDK4-cylinD or CDK2-cyclinE

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20
Q

some genes under the control of E2F/DP1/Rb complex

A

Cyclin A, E, CDK1

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21
Q

loss of Rb gene

A

knock out mice do not survive and undergo apoptosis in several organs, No Rb leads to apoptosis in many cells but not in retinoblasts

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22
Q

mutations equivalent to losing Rb gene

A

mutation sin cyclinD, CDk4, CDK6, p16

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23
Q

several other pathways fo growth converge at the Rb gene product such as

A

TGF beta, transforming proteins of oncogenic viruses binding hypophosphorylated Rb, p53

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24
Q

TGFbeta inhibits cell proliferation by

A

upregulating p27 and p15 (CDK inhibitors) –> defects give rise to cancer

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25
p53 works by
upregulating CDK inhibitor p21, and inducing apoptosis in cells genetically damaged if repair does not occur
26
most common mutation found in 50% of human tumors
p53
27
p53 is activated by
hypoxia, DNA damage
28
p53 binds DNA and transcriptionally upregulates
p21 (G1 arrest), GADD45 (DNA repair) and bax (apoptosis)
29
Li-Fraumeni Syndrome
inherited one mutant allele of p53, 25fold increased incidence of malignant tumors by the age of 50
30
how is Li-Fraumeni syndrome different from Rb mutations
LF patients have a large variety of tumors, develop tumors at a young age, and have multiple primaries
31
How does hypoxia selecto for mutated p53
hypoxia (along with chemo and radiation) activates p53, and the cells die, so in areas of hypoxia where the cell survives, we know that that cell having a mutated p53 is selected bc it did not die
32
p53 and chemotherapy/irradiation
if p53 negative, chemo cannot induce apoptosis so this means resistance to therapy
33
protein similar to p53
p73
34
BRCA 1 and 2 breast cancer rates
80% of familial and 3% or sporadic; also associated with ovairian cancer
35
functions of BRCA 1 and 2
BCRA 1 - regulation of estrogen and androgen receptors, Both - homologous recombination involved in repair of dsDNA breaks in association with RAD51, close association with genes involved at halting DNA synthesis at checkpoints if DNA damage present, While BRCA not involved in may breast cancers could be analogous to Rbp
36
what would accomplish the same thing as BRCA mutation
any damage in the dsDNA repair system - Ub, D2, Rad51, Chek2, ATM, ACEFG
37
Adenomatous polyposis coli
APC gene loss results in the formation of thousands of polyps in the colon with 100% chance that one or more will become malignant
38
APC gene
APC in cytoplasm where it degrades beta-catenin
39
Beta catenein
moves to the nucleus and upregulates transcription of a number of growth promoting genes
40
Mutation resulting in the same thing as a nonfunctional mutation of APC gene
mutation in beta catenin preventing APC binding, also mut in WNT receptor turning it on all the time inducing dissociation of the APC and beta catenin
41
a mutation in APC gene alone
will not cause cancer, but this is one critical hit
42
NF 1 loss
induces type 1 neurofibromatosis, multiple neurofibromas with some malignant transformation - increased risk of acute myeloid leukemia - due to loss of GTPase activity ras is always on
43
NF 1 function
downregulate ras - it is a GTPase activating protein
44
Colon cancer has deletion of
region on chromosome 18 that functions to ragulate axon outgrowth - no known as dependence receptor, signals one way without langand and another way with ligand.
45
colon cancer gene and knock out mice
complete knock out is fatal, but heterozygous knockout shows no tumors_.so the model doesn_t really work in mice
46
colon cancer dependence receptor
no ligand signals apoptosis. With ligand signals something else
47
INK4a/ARF locus
p16 (p16INK4a) the CDK4 inhibitor is coded in this region
48
mutations associated with 50% of pancreatic cancer, esophageal, bladder cancer, and tumors of the head and neck
p16INK4a
49
p16INK4a in cervical cancer
inactivated by hypermethylation, not mutated
50
NF2 codes for
merlin that binds to actin and CD44 (TM protein that affects binding of cell to ECM) and affects ability of cells to maintain stable cell to cell junctions
51
cancers associated with NF2
schwannomas, meningiomas, ependymomas
52
what gene do we think is involved in metastasis
NF2 - rmember ability to maintain cell-cell junctions, so loss of this makes sense that it would contribute to metastasis
53
70% of HNPCC (colon cancer) is associted with
type 2 TGFbeta receptor mutation
54
in the same pathway as TGFbeta what contributes to 50% of pancreatic cancer
SMAD4 gene that codes for a portion of growth inhibitory signaling
55
VHL and cancer
von Hippel Lindau gene mutations associated with hereditary renal cell cancer, pheochromocytomas, and angioblastic tumors of CNS
56
VHL gene product function
ubiquinates hypoxia inducible factor 1 (HIF1) causing degradation. HIF1 norally induces VEGF and PDGF for growth.
57
PTEN and cancer
phosphate and tensin homologue mutated in endometrial Ca and GBMs
58
PTEN function
normally inhibits PI3K/AKT actions promoting cell survival --> so this mutation causes higher levels of PTEN to get cancer
59
Cadherins
promote cell to cell adhesion, mutated in stomach and esophageal cancer, facilitates metastatic capacity
60
WT1 and 2
Wilms tumor
61
WT1
transcription factor for genes involved in renal and gonadal differentiation
62
WT2
unkonwn but in Beckwith-Wiedermann syndrome
63
other candidate tumor supressor genes
KLF6, Patched, TGFbeta system and p21 --> all suspected bc of observed chromosome deletions in certain tumors
64
Bcl-2
protects cells from apoptosis
65
Bax
induces apoptosis
66
Bcl2 fn
Bcl2 lives outside the mitochondria and blocks movement of cytochorme c
67
Bax fn
bax facilitates movement of cytochrome c
68
overexpression of Bcl2 is associated with
B-cell lymphoma -- translocated to IgG promoter similar to Burkitt's
69
HNPCC is associated with
mismatch repair
70
Xeroderma Pigmentosum is associated with
Excision repair - mostly see benign tumors but some can become malignant
71
Telomerer shortening and cell death
teleomeres shroten with each replication and when they get too short it is percieved as a dsDNA break and p53 inhibits entry into S phase. The two ends try and join and the apnormal chromocomes become dicentric that are pulled apart at anaphase inducing new dsDNA breaks. the resulting genomic instability causes eventual mitotic catastrophe and scenscense
72
Telomerase
tumor cells can reactivate telomerase and become immortal -- during the crisis stage of dicentric chromosomes.
73
slide 124
be aware
74
Epigenectic mechanisms - tumor cell DNA
tumor cell DNA is generally hypomethylated and there is promoter specific hypermethylation
75
region scilenced by promoter methylation in colon and gastric cancer
CDKN2a locus coding for p14 and p16. similarly with BRCA1 in brease cancer.
76
Histone modifications
paly important roles in depression of stem cell like genes
77
hyper and hypo methylation
hyper --scilencing, hypo --activating
78
metabolic changes in cancer cells
shift to glycolysis in the face of adequeate oxygen (Warbur effect).
79
reasoning for the Warburg effect
growth advantage for hypoxic tumor cells, dec O2 demand, more O2 for each cell. Lacktic acid fermentation of blocking pyruvate from entering aerobic metabolism alows for shunting fo these carbons to synthesis of molecules other than DNA that are needed for division. Normal cells respond to O2 deprevation with autophagy, tumor cells do not.
80
miRNA
suppress translation --when there is too much, tumor suppressor translation might be affected --when there is too little, oncogene translation might be allowed --> both ways lead to cancer
81
in the sequence of events loss of p53 is a
late event
82
sequence of events
sequence matter, APC initiates, p53 loss allows progression
83
potential gate keepers are
APC, Rb, NF1 --there are few of them and they are tissue specifice
84
Care takers are
BRCA1 and 2, p53 -- enhances mutations of all genes
85
p53 mutation is resistant to
Chemo theramy
86
mutation in BRCA mutation
radiation induces dsbreaks so dna repair enzymes are sensitive to irradiation

Pathology (26 decks)

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