lecture 35 Flashcards
every hour in 2023 =
27 canadians expected to be diagnosed with cancer
which cancer causes most deaths
lung cancer
describe cancer death rates over the years
have decreased
early detection important - before metastasis
name hallmarks of cancer - 6
sustaining proliferative signalling
evading growth suppressors
activating invasion and metastasis
enabling replicative immortality
inducing angiogenesis
resisting cell death
describe ex of sustaining proliferative signals/evading growth inhibition
normal 3t3 (divide 3 times in day) cells = fibroblasts
transformed 3t3 cells = diff shape and can grow on top of each other = bECAUSE src oncogene transforms normal cells to become insensitive to contact inhibition
can cancer be a genetic disease
yupppp
syndromes can be inherited
name the cancers that can be genetically tested for and th genes they look at
hereditary breast cancer and ovarian cancer syndrome = BRCA1, BRCA2
li-fraumeni syndrome = p53
familial adenomatous polyposis = apc
retinoblastoma = rb1
ALLL tsgs
what are oncogenes
positive regulators driving tumorigenesis = becomes hyperactive
what are tumour suppressor genes - tsgs
negative regulators that are inactivated in cancer= loss of function mutations
what are dna repair genes
prevents mutations maintain dna integrity = maintenance
describe tumor virus - rous sarcoma
chicken with sarcoma - removed - grind up - filter - inject to another chicken = now has sarcoma
1910 = peyton rous discovered particles smaller than bacteria could reproducibly induce sarcomas in chickens = led to discovery of tumor virus - rna tumour virus
virus must carry a cancer causing gene
what was first oncogene
v-src = isolated from rous sarcoma - 1970
what are protooncogenes
required for normal cellular function but when mutated become oncogenes and promote cancer formation
like when incorporated into viral genome
describe discovery of proto oncogene
late 1970s = search for related sequences in normal cells and discovered proto oncogenes - c src
describe whole process of viral oncogenes - transcription
retrovirus inserts into cell - reverse transcription and inserts into host chromosome next to proto onco
then provirus makes mistake and transcribes protoonco = c src = now protoonco incorporated into virus
in v src - c term of protein responsible for neg regulation is absent
in repeated rounds of viral infection = proto oncogene becomes rearranged or mutated or both
= produced oncogene = now inserted back into host chromosome
Promotes cancer formation when expressed in normal cells
describe whole process of viral oncogenes - expression
retrovirus infects a cell = provirus inserts near a proto oncogene = strong viral promoter stimulates overexpression of proto oncogene = bad
describe non-Viral transformation of proto- oncogenes to oncogenes
in humans = most proto onco genes activated in absence of viral infection = by
mutations in coding sequences and chromosome abnormalities (increased expression or fusion protein that is a cancer specific form)
what is RTK
receptor tyrosine kinase = cell surface proteins that bind to extracellular signalling molecules like growth factors
binding of singling molecule = leads to phosphorylation on tyrosine residues
ex - activated ras - adaptor molecules bind to receptor and link to ras, ras binds gtp and is activated
describe ras more
gtp bound ras binds raf (kinase) = initiates cascade of phosphorylation events
raf - activates mek and that activates map and then map activated tfs
activates transcription factors that promote growth
describe ras in normal cells
Carefully controlled
sos = gef = stimulated gdp–> gtp exchange = turns on and activates downstream ser/threo kinase
ITS A SELF TIMER
Intrinsic gtpase activity = turns it off
what happens if single point mutation in ras
enough to drive tumorigenesis
ex = GGC –> GTC = gly to val = now gets stuck in active form
ras wild type to ras oncogene
describe oncogenic activation of ras
ras g12v mutation = promotes growth and cascade with no growth signal
are oncogenes dominant
mutant alleles - oncogenes tend to be dom = one copu of mutant allele enough to induce excessive cell proliferation
mutation in single cell - NOT every cells in organism = still leads to tumour
describe burkitt lymphoma (b cell) cancer
reciprocal translocation between chrom 8 and 14 = t(8:14)
what is c myc
tf whose normal function is to promote cellular growth/proliferation = proto oncogene
transcription tightly regulated = only on when needed
what happens to c myc in burkitt lymphoma
myc is translocated so there is a regIG strong promoter near it = now myc is hyperactive
coding sequence of myc not changed
but myc is overexpressed by ig regulatory elements
describe CML - chronic myelogenous leukemia
reciprocal translocation frequently seen in cml
Philadelphia chromosome t(9:22) is observed in 95% of ppl with cml
what is c-abl
protein kinase involved in many cellular processes (proto-oncogene)
describe c-able - cml
causes new protein - affects coding sequences
chimeric protein at molecular level
Recombines and makes brc1-able fusion protein = now new protein
brc1-abl becomes hyperactivated kinase
medicated to target fusion protein = gleevec
