LEC52: Oncogenes Flashcards
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
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
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
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
