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Flashcards in LEC52: Oncogenes Deck (43):

who first proposed oncogene notion?

1) percival potts, 18th century london noticed increased incidence of testicular cancer in chimney sweeps -> proposed that cancer's caused by carcinogens 

2) peyton rous in early 20th century identified a virus that caused sarcomas in chickens, RSV, proposed cancer can be caused by viruses 

these two ideas together became oncogene hypothesis 


what are proto-oncogenes? 

what happens to them to cause cancer? 

specific cellular genes that can become mutated

by carcinogens

or co-opted - by viruses

to trigger tumorigenesis


what is rous sarcoma virus?

first RNA tumor virus to be identified 

its viral genome's oncogene is src; when mutated, leads to cellular transfomration 


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what is a proto oncogene?

a cellular gene within the genome that can be mutated, altered, or somehow manipulated by the virus or by the cancer cell, results in having oncogenic properties, tumorigenesis


what are the oncogenic mechanisms of an RNA virus?

1) the viral genome can contain the oncogene

2) the virus can integrate in a genomic locus that results in aberrant expression of a cellular gene


what is C-src vs V-src?

V-src: version of the oncogene in the virus 

C-src: normal cellular gene, the counterpart of V-src, becomes mutated and thus the oncogene 


what is ALV?

class of RNA tumor viruses whose genome doesn't have a corresponding src 

works by insertional mutagenesis


what is insertional mutagenesis?

mechanism of some RNA tumor viruses, like ALV 

its provirus has a strong promoter enhancer that drives expression of its own genes 

so when inserts randomly in a host genome, often has no effect, but if it inserts upstream of an oncogene such as c-myc, it causes aberrant overexpression, uncontrolled proliferation, oncogenesis 


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mechanisms of oncogene activation in human cancer?

1) missense mutation 

2) gene amplification 

3) chromosomal rearrangement

4) uncommon, but also: regulatory mutation 


what does a missense mutation in a proto-oncogene cause?

constituitive activation 

hyperactive protein, made in normal amounts


what are common missense mutations in Ras? result?

G12V or G13V

these residues are adjacent to GTP binding site

results in loss of GTPase activity, to hydrolyze GTP to GDP 

Ras-GTP is always active, so ERK pathway is always ON -> Cyclin D constituitively high -> E2F active -> cell undergoes uncontrolled proliferation 



will a cell with a Ras missense mutation be growth factor dependent or independent?

growth factor independent - do not need growth factor binding for RTK to be on



what Raf missense mutation commonly occurs in cancer?

V600E mutation

leads to its constitutive Raf kinase activity 

this Raf mutation is commonly found mutation in melanoma



what is frontline melanoma therapy?

Raf kinase inhibitors; prevent ATP-kinase binding 


what is regulatory mutation's result?

normal protein's over produced


broadly, how does gene amplification lead to cancer?

methods of occurence?

single copy of proto-oncogene undergoes amplification due to aberrant DNA replication, leading to increase in copy number 

it's an overexpression of a normal protein 

1) gene in its normal locus is amplified and overexpressed 

2) tyrosine kinase receptor constituitive activation without a ligand

3) amplification of the growth factor - autocrine loop



what is a double minute?

small fragment of extrachromosomal DNA 

are a manifestatin of gene amplification 

this homogeneous staining region contains an amplified particular gene or oncogene

are the result of aberrant replication of a chromosome 



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how are Myc, Cyclin D1, Cdk 4 potentially cancer causing?

amplification of a protein that is normally regulating like Mdm2 or myc or cyclin D can cause gene amplification, -> cancer


how might EGFR amplification result in cancer?

EGFR is the furthest upstream signaler in the ERK pathway; EGF binding causes EGFRs' dimerization, cross-phosphorylation on cytoplasmic side, signaling Ras, Raf, Mek, Erk activation 

If EGFR amplified, localized concentration is high, they cluster, get spontaneous, constituitive, self-activating dimerization

results in Erk pathway activation  


when is EGFR gene amplification common?

lung cancer


when is her2 often amplified?

breast cancer 



what is herceptin?

antibody that binds to her2 receptor, prevents its dimerizing

used as breast cancer therapy for patients w/ overexpression of her2 due to gene amplification


what is autocrine loop?

mechanism of growth factor amplification when the same cell expresses both the growth factor and the receptor, whereas normally growth factors come from other cells & interact w/ the receptor on the cell surface 


ex: PDGF, platelet-derived growth factor



what are mechanisms of chromosomal rearrangements that -> cancer?

1) chromosomal translocation: piece of 1 chromosome reassociates w/ another chromosome 

2) inversion: a piece of DNA switches around within the same chromosome


how might chromosomal translocations occur?

reciprocal translocation between 2 different chromosomes OR inversion within the same chromosome

rearrangements can involve regulatory regions or coding regions 


what is result of a translocation involving a regulatory vs a coding region?

if involves regulatory region: alters expression of a normal protein 

if involves coding region: results in expression of a novel, fusion protein


what part of chromosome does gene rearrangment involving regulatory often involve?

what is the result?

immunoglobulin enhancer or T-cell receptor enhancer 

results in a B cell or T cell lymphoma 



what do B cells do

make antibodies

undergo genomie rearrangements to create high expression of immunoglobulin, high level of transcription through enhancer


what causes Burkitt's lymphoma? 

B-cell lymphoma. cause:

reciprocal translocation of myc gene on chr 8 and immunoglobulin enhancer on chr 14


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what does this show


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reciprocal translocation causing burkitt's lymphoma is: 

c-myc (coding region) on chr 8 and Ig enhancer (regulatory region) on chr 14


what causes follicular b-cell lymphoma?

reciprocal translocation of bcl-2 gene on chr18 and Ig enhancer on chr14 

results in overexpression of Bcl-2 which inhibits apoptosis 

thus suppresses cell death 


what causes parathyroid adenoma?

intrachromosomal inversion of chr11

puts promoter of parathyroid hormone gene upstream of cyclin D1 gene 

puts cyclin D1 under parathyroid hormone promoter control, leads to overexpression of Cyclin D in parathyroid, constituitive E2F transcription 

this is a cell-type specific cancer, as promoter is only activei n parathyroid cell


what does gene rearrangement involving coding regions result in?

transcriptional over-expression 


what creates a fusion protein?

chromosomal rearrangement

overexpression of fusion protein can -> cancer


what is the philadelphia chromosome

chromosomal abnormality of CML 

results from reciprocal translocation of c-abl gene on chr9 and bcr gene on chr22 

results in expression of novel, fusion protein, Bcr-abl 

results in Abl kinase being constituitively active


what is Abl

a tyrosine kinase on chr9 w/ an amino terminus that normally regulates kinase domain on the C terminus 

Bcr-abl fusion protein makes kinase constituitively active because loses C terminus domain in fusion

thus get constitutive Abl kinase activity in CML 


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what is Gleevec/Imatanib, how does it work?

inhibitor that's highly selective for Bcr-abl fusion protein; blocks Bcr-Abl binding to substrate protein, thus cannot have ATP binding and activating phosphorylation of substrate protein 

it prevents leukemia 


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why is Bcr-Abl protein usually active? result?

Abl loses its ability to regulating its tyrosine kinase activity when fuses w/ Bcr

so it undergoes activating phosphorylation

results in signal for cell proliferation, survival, so leukemia


are fusion proteins a big drug therapy target?

no, because chromosomal rearrangements involving coding regions resulting in fusion proteins like Bcr-abl in CML cases are very rare 



what occurs in APL, acute promyelocytic leukemia?

reciprocal translocation of PML gene on chr15 and retinoic acid receptor gene on chr17 

results in expression of a novel, fusion protein, PML-RAR


what is the idea of oncogene cooperation?

full tumorogenesis requires several genetic changes 

a single oncogene activation isn't sufficient for a person to get cancer 



how can cooperating oncogene principle be shown experimentally?

if incubate primary oncoblasts with myc - oncogene - or E1A - viral product that's oncogeneic - either myc or E1A alone doesn't yield transformation in an anchorage independent environment 

Ras alone also doesn't transform cells 

however myc or E1A plus Ras gives cooperation

ras shows: need a 2nd oncogene to observe transformation

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how can cooperation btwn 2 oncogenes be shown experimentally in vivo?

mouse model: 

mutant, activated Ras expressed in mouse mammary gland results in some tumorigenesis; overexpression of myc has minimal tumorigenic effect; but Myc overexpression at same time as mutant, activated Ras, tumor formation is accelerated


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