oncogenes

what kind of genetic damage is cancer?
non-lethal genetic damage
what are oncogenes and tumor suppressor genes considered?
regulatory genes
how was the transmissible component of cancer first discovered?
P Rous found that if material was injected from a neoplasm of one chicken into another, the 2nd chicken would also develop a neoplasm
what was the next study after the chickens where cancer was shown to have a specific genetic component? what gene was found to be involved?
DNA was extracted from a human bladder carcinoma, transected into mouse fibroblast cells, and the mouse fibroblasts were then transformed; resulting in a tumor. after sequencing the ras gene was found to be involved
why were retroviruses studied in relation to cancer research?
they could create gene recombination, leading to transformation of the animal cells they infected by picking up DNA and changing it slightly. this was proven by blasting eukaryotic and retrovirus DNA against each other and seeing the similarities
how were oncogenes first categorized?
oncogenes corresponding to different cancers were given 3 letters with V in front, today oncogenes are named the same way but the V is replaced by a C
what are protooncogenes?
normal genes that have the potential to become oncogenes
what are some actions of oncogenes?
oncogenes can phosphorylate serine, threonine, and tyrosine. they can activate GTPases, and control DNA transcription
where can oncogenes act?
anywhere inside or outside the cell including growth factors, growth factor receptors, membrane proteins, cytoplasmic proteins all acting on nuclear factors
can increased growth factor production alone cause neoplasmic transformation? can tumors make their own growth factors?
no, but mutations in genes encoding growth factors play a part in cancer formation. for example, c-sis encodes the B chain of PDGF and is often involved with formation of astrocytomas and osteosarcomas. tumors can make their own growth factors via autocrine stimulation.
what are many growth factor receptors? how do they function? what happens when they become oncogenic?
many growth factor receptors are transmembrane proteins with external ligand binding and an internal tyrosine kinase. upon growth factor binding, dimerization occurs and substrates are phosphorylated. the oncogenic version of these receptors are associated with persistent dimerization/activation w/out binding to the growth factor = constant mitogenic signalling
what is a common mutation other than self-dimerization that can lead to abnormal growth factor receptor activation? what are some growth factors this happens with, and the lung cancers they are associated with?
the overexpression of growth factor receptors due to gene amplification. this can happen when different alleles are amplified, leading to 4-5 gene products being made. the transcription factor c-myc often undergoes amplification. 3 members of the epidermal growth factor family are associated with the following cancers: C-erb-B1 – 80% of lung CA, C-erb-B2 – adenocarcinomas, C-erb-B3 – involved with breast CA.
are mutations in the protoooncogenes coding for growth factor a common reason for abnormal growth factor receptor activation?
no, but it does happen
what are some general ways that growth factors are involved in cancer initiation on cell membranes?
increased growth factor, increased growth factor receptors, defective growth factor receptors, transducer mutations
beyond increased cell division, what is the result of increasing growth factor receptors abnormally?
angiogenesis and inhibition of apoptosis
what does the drug tarceva do in terms of abnormal growth factor stimulation?
tarceva inhibits the EGFR tyrosine kinase so that normal cell growth function may be restored
where are the signal transducing proteins located? what is a key one?
the signal transducting proteins are found on the internal part of the cell membrane, the key one being ras which is activated upon activation of the growth factor receptors.
what is ras? what happens if it is mutated?
ras is a signal GTP (guanine triphosphate) transducing protein. ras itself is a GTPase that cleaves GTP -> GDP. ras is inactive when GDP is bound to it, but upon growth factor stimulation, ras is activated by exchange of GDP w/GTP. if mutated, ras can’t cleave GTP -> GDP, and it will stay active, stimulating MAP-kinase activity -> leading to activation of transcription factors in the nucleus = cancer.
what is the single most common abnormality of dominant oncogenes in human tumors?
ras mutations, 10-20% of all human tumors have mutant ras
what is a GTPase activating protein (GAP)? how do they affect mutant ras?
GAPs bind to ras and increases its GTPase activity (by 1000x – it is considered a tumor suppressor). they still bind to mutant ras, but do not increase its GTPase activity
are cyclin-dependent kinases affected by ras? what do they do?
cyclin-dependent kinases can be activated by ras independent of having to go through the MAP kinase pathway. cyclin-dependent kinases are constitutively expressed on the nucleus waiting to be bound by cyclin, that when activated sent the cell through the replication cycle
what are some nuclear transcription factors? what do they do? what is a major one involved with CA?
oncoproteins such as eg, myc, myb, jun, and fos are nuclear transcription factors that are “early response genes” and first to be activated when signals are being sent to the cell for it to divide. they are localized in the nucleus and myc specifically is commonly involved with human tumors, usually due to abnorml amplification
what helps to control myc activity?
max and mad form heterodimers that stimulate transcriptional activity by binding to DNA. max-max homodimers are inactive, myc-max heterodimers stimulate transcriptional activity, and mad-max heterodimers repress transcription
can mutations in genes encoding cyclins/cyclin-dependent kinases cause cancer?
yes, cyclin D and CDK4 are overexpressed in many cancers specifically, they bind early in the cell cycle (G0->G1), and stay permanently bound
are cyclin D and CDK4 constitutively expressed?
CDK4 is constitutively expressed, cyclin D is made for each specific signal
what do cyclin D/CDK4, cyclin D/CDK6 and cyclin E/CDK2 do collectively?
the action of these three kinases phosphorylates the retinoblastoma (Rb) encoded protein, which is usually unphosphorylated and keeps cell growth static. phosphorylating retinoblastoma deactivates it, and it releases transcription factors, E2F in particular (which leads to DNA synthesis)
what happens if the Rb encoded protein is mutated/deactivated?
the cell will just go from G1 to S phase without any regulation
would problems with cyclin D/CDK4, cyclin D/CDK6 and cyclin E/CDK2 affect phosphorylation/dephosphorylation of retinoblastoma?
yes each one is important
what do cyclin dependent kinase inhibitors do?
these tumor suppressors compete with cyclins binding to CDKs at different points in the cell cycle to prevent Rb encoded protein phosphorylation
where is the Rb encoded protein located? when is it underphosphorylated? hyperphosphorylated? what is this a function of
the Rb encoded protein is underphosphorylated (active form) in G0 & G1 and hyperphosphorylated (inactive form) in S, G2 and M. this is a function of CDK dependent knases
what can be the result of changing the structure of a gene? what are ways this might happen?
changing the structure of a gene can result in the gene expression being disregulated/changed. this can happen via point mutation, chromosomal rearrangements (translocations: common/inversions: less common), and gene amplification
what is the result of changes in regulation of gene expression?
if gene expression is changed there can be enhanced or inappropriate production of a structurally normal protein
what oncogene is the best example of a point mutation?
the ras oncogene where several different mutations have been IDed; all result in decreased GTPase activity and poor GAP stimulation of GTPase activity = resulting in ras remaining its active GTP-bound form. 90% of pancreatic adenocarcinomas contain a ras point mutation
how does translocation cause a burkitt lymphoma?
an inactive myc gene is translocated from chromosome 8 to 14 next to IgG heavy chain gene and is activated every time IgG is turned on = B cells growing out of control, forming a lymphoma (burkitt)
how does translocation cause chronic granulocytic leukemia or CML?
the break point cluster region (bcr) on chromosome 22 is a fragile region that allows for a lot of translocation events, such as the abl gene from chromosome 9 which codes for tyrosine kinase in the cytoplasm -> leading to the amplification of tyrosine kinase activity (this translocation is called the philadelphia chromosome)
how is the philadelphia chromosome treated?
there is a drug (imatimib mesylate) which fits into the active site of the abl protein and competes for ATP, shutting down the kinase activity
what does c-myc amplification in hepatocellular CA predict?
an unfavorable prognosis
what does a homogenous staining region demonstrate? double minutes?
both indicated amplification of a specific gene
how is n-myc gene amplification involved with neuroblastoma formation?
in the formation of neuroblastomas, the Rb gene is often deleted, leading to the amplification of n-myc
what is seen with myc RNA levels after a mitogenic stimulus? relative cell #?
myc RNA levels initially skyrocket at a mitogenic stimulus and then drop, while relative cell # will rise slowly
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