Cancer Flashcards
neoplasm
tumor-any abnnormal new grwoth of cell
genetic basis of cancer
most cancer-causing mutatons are somatic
mutagens are mostly environmental
Need mutliple mutations in many pathways
-major target is cell diviosn
Clonallyrelated cancer cells
all tumors begin with single cell-increase in size as population of tumor cells grow
accumulate aditional mutations-increase malignancy
-hetergenicty of cells
Contact inhibition
cells lose thjier abilty to respond to ECM and neighboring cell signals
-sto cells from prolifeating and migrating
how loss of contact inhibition
loss of cadherins-break link to other cells
metallopretases0degrade ECM and facilitate tissue invaision
g1/s transition
any pathwa that messes with this may cause cancer
tumor supressor genes meaning and 2 typse
prevent tumor dev
- caretakeer-protein prevents damage or repairs DNA damage
- gatekeeper-induce apop or restain cell diviosn
ocnogene
prteins promote cell growth and division
gain of funciton mutation leads to cancer-release of control
tumor represor mutations
receissive-need to lose both copies
-loss of heterozygostiy
need loss of function to iactivate protein
appear domoinant in pedigrees
exmaples of caretakes (3) and gat keeper (2)
MLH, BRCA, ERCC1
Rb and p53
rb/p53 fucntions
rb-controls g1/s transition
-53 halts cell di]viosn/initatse apoptosis in response to DNA stress
repair patway of MLH, ERCC1, BRCA1/2
MMR
NER-XP
DSBR-breast cancer
two rb disease
sporadic-single tumors in one eye of one person
familial-usually bilateral tumors (possibly multiple in one young). younger age, multiple family members affected
Two hit hypothesis
unilateral tumor-expected if two events needed for tumorto start forming
-loss of heterozygosity
bilateral-one even is required
how to get loss of hetero
chrom loss, duplicaton, mitotic recomb, gene conversion, deletion, epigentic, etc
p53 and cancer cells
loss of p53 renders cancercells immun toapop
stimulate trx of factors that block cell cycle (CDK inhibs/pro apoptotic proteins)
Converence point for many pathways
how to stimulate p53
DNA damage-protein kinases
growth factors-arf protin synthesis
arf protein
alternative reading frames-transcribed from DNA that encodes CDK inhibitor
pro apoptotic
MDM2
binds to ARF-destbilizes p53 since ARF cant stabilize
MDM2 is antiapoptotic
p53 structure
p53 is intriniscally unstable-stablized by DNA damage
- no inherent tertiary structure
- oncgogenic mutations can block DNA binding domain
- drugs are used to stablize p53
proto-oncogene
normal gene that can trn into an oncogene as result of mutations or increased expression
two tyes of oncogene
viral-v-src-get DNA from cell, mutate it, put into another cell
cellulr oncogene-leads to continuous activity of protin GOF (dominant)-or LOF (recessive)
cell cycle control pathway GF to end
growth facotors GFR-TK ras protein kinase cascade TF's cyclin and cdk-inhibits RB Rb-inhibits nex step- E2F/G1/S
all of ones where not inhiibited-stimulate next step
all of these except RB and G1/S are oncogenes
obviously many places for mutaions
cell cycle control pathway tumor spupressor genes
NF1 (ras GAP)-supreses ras
TGfbeta-TGFbeta receptors-TF-CDK inhibtor
-inhbits CDK
mTOR pathway, what are oncogenes or tumor sups
pip2-pip3-pkb-tsc-mTOR-protein synthesis/growth
pip2 to 3-P13K
pip3 t2-PTEN
oncogenes-PKB, mTOR, P13K
tumor sup-TSC, PTEN
activaton of c-myc, c-abl, c-ras
myc-overproduction
abl-self activation-no need for normal reg stim
ras-prevent inactivation
c-myc what it does and how mutation occurs that leads to problem
stimulate cell cycle
-amplified in many tumor
number of copies can be increased (gene amplification) and chromasmal translocation can occur-put in front of srong promoer
how t diagnose c-myc rpoblems
FISH
see mny repeats-double minute chromasomes?
also can see small dots where notmal should be
c-myc disease
burkitt lymphoma
tumor of b lymphoytes
-powerful enchancer to make b lymphoytes
translocate c-myc into hat region-much more trx
c abl disease+ how diagnose+etiology
CML
philidelphia chromasome
translocation of 9 to 12, small p[art of 22 breaks off (philidelphia)-other part goes onto chromaosme 9
-attaches behind BCR-no more protein kinase to turn on (contintuivilty active)
BCR
breakpint cluster reion-on chromasome 22
-creates protein that does nto have to be activated
c abl structure
sh-src homology-oncogene withprotein kinase activity
sh2/3-regulatory-inhibit kinase untl they are modifed by activatd inhibitor
sh1-portien kinase domain
activation loop-poly peptidee chain in sh1 domain that occludes active site-can be phophorylated toallow substrateto bind
——add 2 oligomerzed bcr in front-activate kinase that can do whatever it wants now
gleevec
binds to and stabilies inactive confomrmatin of c-abl
oncogene addiction
glevec
main component of cancer driving pathay makes a bottleneck-this gene becomes the king becuase others are gotten rid of because this one is the best for abnromal environemt-target this gene
ras + GAP abilites
active when bound t GTP, inactive at GDP
- two gap actvites (intrinsic and extrenisc by GAPs (like NF1)
- intrinsic is not as effecient as GAPs
- need both to ensure ras sigals properly
GEF
replaces GDP by GTP
GAP
gtpases-ras (intrinsicly) and NF1
switches GTP to GDP
proteins with ras homology domain
alot-results in cell growh, cell adheion, ant apop, membrane traffic, etc.
oncogenic mutation in ras
gly 12 and gln 61
0reudece GAP (gtpase) activty of ras
0spends more time active
