Lecture 31 Flashcards
6 important hallmarks of cancer
- sustaining proliferative signaling
- evading growth suppressors
- activating invasion and metastasis
- replicative immortality
- angiogenesis
- resisting cell death
describe normal vs transformed 3T3 cells
normally stop growing when confluent bc of contact inhibition
with Src oncogene, no contact inhibition so will keep growing
what 2 hallmarks of cancer are involved in transformed 3T3 cells?
- sustaining proliferative signals
- evading growth inhibition
example of cancer that is genetic disease
Li-Fraumeni syndrome
genes involved in breast and ovarian cancer
BRCA1, BRCA2
gene involved in Li-Fraumeni syndrome
p53
gene involved in familial adenomatous polyposis (colorectal cancer)
APC
gene involved in retinoblastoma
RB1
what are oncogenes?
activated to drive tumorigenesis (positive regulators)
what are tumour suppressors?
inactivated to drive tumorigenesis (negative regulators)
describe involvement of DNA repair genes in cancer
prevent mutations to maintain DNA integrity
describe discovery of RSV
- crush up sarcoma from chicken
- pass filtrate thru fine-pore filter that does not block viruses
- inject filtrate into chicken
- chicken develops sarcoma
therefore, RSV carrying cancer-causing gene
what is the cancer-causing gene in RSV?
v-Src
what kind of gene is v-Src?
oncogene
what is c-Src?
the proto-oncogene
what is a proto-oncogene?
required for normal cell function but when mutated become oncogene
how do retroviruses make oncogenes? (5 steps)
- virus infects and creates provirus next to proto-oncogene
- cell transcribes provirus and proto-oncogene
- when virus reproduces, proto-oncogene is incorporated into virus
- with repeated rounds of viral infection and replication, proto-oncogene becomes rearranged/mutation (this is when it becomes a problem!)
- now oncogene is inserted back in host chromosome and promotes cancer
alternative way how retroviruses make oncogenes
- virus infects and creates provirus next to proto-oncogene
- strong viral promoter stimulates overexpression of proto-oncogene
are all proto-oncogenes activated from viruses?
no
2 ways (other than viruses) that proto-oncogenes are activated?
- mutations in coding sequences
- chromosome abnormalities
2 chromosome abnormalities that lead to proto-oncogene activations?
- increased expression
- fusion protein
what is RTK?
cell surface protein that binds extracellular signaling molecules, leading to phosphorylation of tyrosine residues
describe how RTK activates Ras
- growth factor binds RTK
- adaptor molecules bind the receptor, linking RTK to Ras
- Ras binds GTP and is activated
- GTP-Ras binds Raf to cause phosphorylation cascade
- activates TFs that promote cellular growth
what kind of protein is Ras?
GTPase
what kind of protein is Raf?
kinase
describe normal regulation of Ras
normally has intrinsic GTPase activity so GTP-Ras automatically turns into GDP-Ras
why is it important that GTP-Ras can automatically become GDP-Ras?
so it’s not constitutively on and activating genes for cell growth
what causes Ras to become dysregulated and drive tumorigenesis?
1 point mutation in AA 12 turns Ras from proto-oncogene to oncogene
describe oncogene form of Ras
stuck in GTP-Ras state so it is constitutively on
are oncogene mutations haplosufficient or haploinsufficient? why?
haploinsufficient because oncogene mutations are DOMINANT
describe oncogene mutants as dominant
mutants creating oncogenes are DOMINANT –> 1 copy of mutant allele is enough to induce excessive cell proliferation
difference btwn cancer mutation and mendelian genetic diseases
cancer involves mutation in single cell to make disease
other genetic diseases inherited by mendelian genetics affect every cell in an organism
what causes Burkitt lymphoma?
reciprocal translocation btwn Chr 8 and Chr 14 in B cells
what gene is involved in Burkitt lymphoma?
c-Myc
what is c-Myc?
TF whose normal function promotes cellular growth/proliferation (proto-oncogene)
what chromosome is Myc on?
chromosome 8
describe how translocation leads to activation of c-Myc into oncogene
regulatory element of chromosome 14 is for immunoglobulin
when translocation, this regulatory element is upstream of Myc and leads to overexpression of Myc –> Myc loses tight regulation
what causes chronic myelogenous leukemia?
translocation btwn chromosome 9 and 22
what is c-Abl?
protein kinase involved in cell survival
what is produced in the CML translocation?
Bcr1-Abl chimeric protein is made and is a HYPERACTIVATED KINASE
why is it easy to target Bcr-Abl?
bc not found in normal cells
