Genetics Monday 4/7/08
cancer
second to heart diease
differences who get cancers
breast cancer local tumor-
distant tumors- single location rate goes down
liver cancer—> dead
metastesize
genetics differences between cancers
melanoma-
darker skin is protective against mutagen.
cancer strikes when older
Gene- Restinoblastoma cancer of the eye
how do get cancer?
two hit model for cancer prevention genes
diploid we have to copies
inheritance of the bad copy
mutant for being RB much more chance to get the cancer
only one mutation to lead you no functional copies of RB
nondisjunction
two copies identical
mitotic recombination
simple point mutation
only one functional copy
one mutation to get rid of the functional copy of the RB
gene conversiotn when chromosome- recombination
cross over
single stranded tail of one of the chromosomes
two overhanding strands of tails
one of them invades the double stranded blue chromosesm
replaces the second strand of blue chromosomes
end result: cross over one green one red hamlet
DNA mismatch
hybrid molecule
randomly picks
gene conversion three copies of little a allele
gene conversion
mitotic recombination uses the mechanism
section 6.5
mismatch repair
RB Minus homozygous
can proliferate and become the tumor cell
cancer cells character
six specific
almost all cancer cells
sustained angiogenecis- tumor forms induce blood vessel growth need o2 inducing blood vessel growth
Evading apoptosis- if picking up too many mutation- cell suicide cancer
self sufficen in growth signal- produce their own growth signal or become efficient
Insensitivity to anti- growth signal- uncontrolled have to ignore the signal
tissue invation and metastatis- cells can move on and mestastize
limitless replicative potential- when chrom replicated- shorter- too short → apoptosis
cancer cell bypass
how cancer cell avoid to shut cell of that proliferate
what about stem cell- many more division
growth factor recepters- ligands- downstream will get activated.
cancer cell can pick up mutation
ligand independent factors
GFR mutation
Autocrine signaling self sufficient for growth signals
insensitive to anti growth signals
contact inhibition- stop dividing when contacting cell closely.
ignore apoptotic signals
loss of cell adhesion free from tumor to go to other places. Junctions have to be lost- you can go to metastesize.
ability of the cell to divide forever.
everytime cell divided
Telomerate-TERT functional unit- adds DNA to the ends of chromosomes after replication- so you can compensate- telomere sequence.
tert is only on germ line (active)
cancer cells – turn on the enzyme that should not be on
limitless replicational potential
abornomal production
how does telomerase do this trick
protein and nucleic acid that it carries- bind to the end of the chromosomes
cell has gone through the dna replication
DNA POLYMERESES
Uses RNA template
To bind to the end \
uses the temp to fil the strand of DNA
hopp farther down
Does it put the right sequence- it’s the right sequence
no multiple telomerase
Linear chromosomes which al the genes are in the middle of the chromomes
not disrupting the genes
how cells die – shorttend the DNA into the gene
structure of the telomerase
only cell in the body cell germ line and any cancer cells
angiogenesis- six characteristics
induce the formation of more blood vessels. Produce blood vessles
signal that promote angiogenes
VEGF recepter epithial cells that produce positive signal
induces the endothilal cell to produces blood vessels
DLL4 negative signal
prevent blood vessel growth blood vessel formation
balance Between DDL4 and VEGF that bring actual blood vessel growth
where does the signals come out?
Tumor cell also has the transmembrane
localize DLL4 signaling
Form blood vessles in the direction you need
lot of drugs againt angiogenesis
entirely body reforming making
total angionesis
blood supply to tomor and also other places in the body
VEGF stops all angiogenesis
PIGF – placental and tumor cells
next big question
six charachteristics
order of the mutations
does It have to have the mutation?
mutaiton that can happened later for tumor become fully capable
no specific order of mutation that can
cell divisiton picks up mutation
cell contiues to replicate
1st 2nd 3rd and forth
point- aquiring increase the rate at which the cell prolifereate
early mutation make the cell divide to much to make the cell incapable of
more cell proliferation necessary for the cancer
liver cancers have different histology
color cancer
one cell picks of mutation APC gene slightly changed morphology
third mutation
P53
Invasive carcinoma
Loss of p53
pick up mutation when loosing the chromosomes
tumor cell from HENritetta Lacks
HELA cells
some of the biopsy- peti dish with nutrients
cancer cells pick up mutation could grow in dish when they have food
cervical cancer cells
1st cancer then live in the dish
used for biomedical research
how do translation, cell cycle and polyvaxyly
Biomedical ethics
jhu.edu
normal karyote for the cell
spectral karyotype
each chromosome different color
two greens
Cancer is not just gene mutation
genomic stablitly – massive
Cancer genes are not just mutated
unstable genome and cell mutation we will study
all chromosomes are stained- all karyote
all different number of copies
bladder cancer
Genetic workshop
3 point cross
pen vs ept
mutation
Robertsonian translocation
Mitochondrian
Prions
Sup35
RB
Gene conversion
Cancer
Penetrance/ expressivity
Low penetrance
Autosomal or sex linked dominant or recessive
Mitochondirail inheritance
Sons don’t pass it down along
What are the type of mutations,:
Neomorph
Anti
Hypo hyper
Haploinssuficeint
Null
Gene shorter links hypermorph shorter legs
Look at what the gene does
Null non functional
Phenocopy- xzavior same phenotype as the genetic disease but not caused x indivdual genetics
Multfactorial- breast cancer
BROC1 and 2 cancer prevention genes only for breast cancer
Balanced and unbalanced robersonian translocation
High penetrance 100% everyone would have it.
Low penetrance : 3 or 4.
Meiotic nondisj in 1 or 2
Anaphase 1 and 2 and know the number of chromosome
Monosomy and trisomy and look at the diagram
Down syndrome
Retinoblastome CML chronic myologenis leukemia
No viability too much of 14 or too little of 14
Mitochondrial diseases
Cardiac muscle lots of mitochondria more atp is needed
Any tissue that requires mitochondria
Inheritance in yeast
Heterplasmic some good some bad
Retinablastome multifactorial
Gene conversion
Mismatch big a A
Invasion of single stranded DNA into double stranded DNA
Holiday junction
Tertiary possible every cell division
Gene conversion
Exceptional female white
She had three six chromosomes
Number of X
1 x male
3x female
XYY dead
XXY exceptional female
Two while eyes XW x XWy
No XXY
No XX
78 c
88 B
106 A
PRIONS- Transmissible spongiform
protein based system
how proteins strucuture formed
1st primary structure
3r structure folder
how protein folds
intermediate lower energy-> folded lowest energy
intermediate final structure stable conformation stable not final
can interchange with the intermediate
prions- diff kind based on the proteins gnene PRNP
wildtype C structure
second structure that is stable but no biologically active
alpha hecices into beta plated sheet ( orginal more alpha helices)
what is happeing with prion shaped proein?
PRPSC abnormal shape good +bad ---> bad shaped
SC abnormal
PRNP- prions are normal
in human is callye PRNP
abnormal can cause disease, getting rid of PRPC
Kuru epidemiology
women were effected
incubation period
******* no nuclide acid in the aget virus RNA genone
enzyme that disovler
conclude infections protein
cruetzelf jakon disease
@@@@@@@@@@@@@
prions resistance to protease- to get rid of misfolder protein
most protease activity ( mostly resistant)
sporatic
acquired – envirinment
familia
varient- eating food contaminated with prions
CJD- Cruetzfield jakob diseasel
different infection- propagation- and disease properties
heterozygous- different allele (2) rate dramaylly slowed down
human prion progien is compsed of 253 amino acids. There are two common allele which inserts valine or methionine at postion 129
Beiing heterozygous
M and V allele
differner race of people
mouse prions
IE not internet explore
Insuff
hamster- hamster E
hamster – mouse IE
Hamter- mouse that makes the hamster prions- E
trans mouse- mouse IE
--->E
mouse – hamster IE
mouse mouse E
Mouse – mouse trans IE
trans mouse – hamster IE
mouse trans ( hamster gene ) and got prions can pass to another mouse
prions are very noninfections across species barrier
but environment of prions
history where it was formd? Org? can effect prion shape.
multiple misfolded, disease causing conformations
familia fatal insominia FFI
PRNP gene allele misfolded prion gene
thalamus FFI attacks thalamus
FFI single mutation in Amino acid 178
chronic wasting diease
CWD in deer infectionous
yeast
sup35
truncated adenine systnths enzyme made
non sense suppression eveyatal substition o f an amino acid
Sup 35 yeast prion gene – prion like confirmation and aggregate= cant act at stop codon.
Molecular for aggression of the prions
structure for the shape when the prions are aggerateion of htat protein
cannont function when it aggeratge
what was the point>?
point to prove proein folding problem
misfolded protein
adenine biosysyteh.
sub35 fuction- recognize the non sense in the middle of the gen ewe get the trunked version whcihc is red
induce the prions shape of the j
prion with yeast. Sub35 no longer function when
adenine biosynthesis gene.
white non function sup35
GnHCL cause protein folidng aloow refolding
guanine hydrochloride
unfold all the prions and let them refold majority
precurser build up when you make the truncated enzyme.
5mM G
