Sustaining Proliferative Signalling W6 Flashcards
How do normal cells control their growth?
through the cell
cycle and growth factor receptor signaling
G1
Intermediate phase
Occupies time between end of mitosis and beginning of DNA synthesis
G0
Resting phase
If no growth factors present then cells go into G0 / resting
Cells stay here for days, weeks, years etc
Before a cell begins DNA rep it must….
Ensure tht is is biologically ready
Soo cellular monitoring takes place in G1
During this the cell review the cellular environment to ensure the conditions are appropriate for replication
If there is growth factors then the cellular environment cycle will proceed
If no GF then will go into G0
Name some growth factors and their
receptors?
• Epidermal growth factor, Transforming
growth Factor a: EGFR
• Hepatocyte growth factor receptor-c-met
Receptor
• Many others: FGF, VEGF, KGF etc.
EGFR signalling
In the presence of ligand the EGFR come together and form homodimers or heterodimers
Receptors are then phosphorylated
Specific adaptor molecules allow activation of target genes
Activated receptors undergo endocytosis
Result in nuclear activation of gene
Protooncogenes
Genes that regulate normal cell growth
What is cancer
Abnormal growth of cells in an uncontrolled way that can spreads or metastasise into other tissues
RAS proto-oncogene product
RAS proteins
- small Gproteins
- involved in GTPhase reaction cycles
- relay a growth signal from a GF on the cell memb to a cascade of tyrosine kinases
Mutation of RAS protocol-oncogene
Just one single amino acid substitution affected the function of Ras to convert it from a proto-oncogene to an oncogene!
Mutations in the Ras gene are found in 30% of human cancers
Weinbergs experiment
Took cells from someone with bladder cancer, isolate the DNA from tumor and transferred DNA into a line
It looked the same under microscope apart from a few neoplastic.
A few transformed into a colony - the morphology changed
Injected the neoplatic colony cells into a mouse and a tumor formed
Showed that these cells can cause a tumor
He was able to isolate the human genes form the house and then confirmed that RAS occurred in cancer
Functional consequences of RAS mutation
Pathways is activated regardless of if there is a ligand or not
Never go into G0
The G protein is stuck on
Gene amplification
Too many copies of a gene so too much of a product
Gene arrangements
promoter in wrong place so normally a weakly expressed gene can be expressed at high levels
Large structural deletions
deletions in receptors sequences e.g. truncated EGFR
Subtle mutations
a single nucleotide change e.g. Ras
HER2
is amplified and overexpressed in about 25% of breast tumours
Trastuzumab
humanized monoclonal antibody, blocks HER2 activity. 70% don’t respond-resistance.
Cetuximab and Panitumumab
are monoclonal antibodies that block EGFR
activity (CRC)
chronic myeloid leukaemia-CML
• accounts for 15-20 percent of all leukaemias
• CML was the first malignancy in which a specific chromosomal abnormality (the Philadelphia chromosome) was identified.
• Characterization of the molecular consequences of this chromosomal abnormality identified an activated oncogene, Bcr-Abl, as the cause of this disease.
BRC
Chromosome 22
Abl
Chromosome 9
Philadelphia chromosome
Fusion of Abl and BCR = BRCABL oncogene
