Molecular Genetics of Cancer Flashcards
Mutations of tumor suppressors are mainly what kind of cellular component?
transcription factors
an oncogene is mutated via point mutation is usually known as a?
gain of function mutation
What is the only naturally occurring growth factor oncogene?
sis
What does sis encode for?
PDGF
Polycythemia vera and Erythroleukemia are mutations involving what receptor mutation?
gp55
HPV is inappropriately stimulated by what receptor?
E5 leading to sustained activation of PDGF receptor
Non-muscular tropomyosin is involved with what chromosomal translocation?
Trk receptor kinase
located in the cytosol after change
Many breast cancers are due to ?
HER2 gene over expression
Treatment of HER2+ breast cancer
Herceptin=only extend life expectancy by 5 mo
What induces GTP hydrolysis of the Ras?
GAP
What has the capability of activating Ras?
SOS has GEF activity
Ras then can activate the what pathway that phosphorylates what 3 things in order?
RAF>MEK>ERK
What amino acid is changed to convert Ras into an oncogene?
postion 12 amino acid to GLY=leaves RAS active
C-Src is normally activated at Tyr position at C-term 527 by?
de-phosphorylation
In Rous Sarcoma, Src has a deletion at terminal?
C-term position 18 producing v-Src and leaving it active
C-Fos and c-Myc are
transcription factors
What phase of the cell cycle does c-myc and and c-for encode genes for?
Progression through G1 and G1 to S phase
Burkitt’s lymphoma where is the c-myc gene translocated from and to where?
CH 8 to CH 14
What does the c-myc translated gene use to encode its protein products?
antibody enhancer
High expression and localized duplication of the translocated myc gene can
lead to increased expression of myc
Non-Hodkin’s Lymphoma aka
Burkitt’s lymphoma
folicular lymphoma involves
a translocation of bcl2 gene on CH 18 that fuses together with an antibody enhancer on CH 14
bcl2 in Burkitt’s lymohoma is produced by antibody enhancers causing
increase in anti-apopotosis
What would increase the cell cycle abnormally?
point mutation to a cyclin or loss of tumor supressor
Tumor suppressors involved for the restriction point in G1 pathway?
p16 and Rb
TGF beta is
a tumor suppressor
TGF beta induces p15 that leads to the synthesis of what
collagens and PAI-1
Tumor cells display the following qualities
increased metabolic activity enhanced glycolysis suppressed OPP high NAs, fatty acid, and proteins glutamine addicted
Glutamine is necessary for what specifically in tumor cells?
replenished the intermediates of TCA cycle
In a normal cell with DNA damage, what is activated by the DNA damage>
p53
What is then in turn secreted by this activated substance that responds to DNA damage?
TIGAR inhibits F 2,6 BSP from stimulating PFK1 and PGM inhibits GA3P DH rxn
What is a necessary enzymes for the PPP in the oxidative run?
G6PD and NADP+ reducing to NADPH
R5P will stimulate
GA3P and F6F
In tumor cells, the oxidative pathway is blocked, via tumor enzymes
PKM2 and TKTL1
PKM2 acts to
let glycolytic intermediates build up and increase in flux through the non-oxidative pathway
TKTL1 GA3P and F6P to
R5P in the non-oxidative pathway to create DNA and RNA
F1,6BP inhibits
the oxidative pathway inhibiting G6P
If there is a mutattion at p53, what will happen to glycolysis
there will be less NADPH produced from the PPP due decreased inhibition of the glycolytic pathway
Glycolysis depends on the recycling go what?
NAD+
Glutamine will do what
replenish the TCA cycle with necessary intermediates and produce NADPH
Important intermediates for anoploetic rxns
Malate»>lactate
citrate»>fatty acid syn
Alpha keto gluterase for protein syn
VDAC bound to HK-2 bound to ATP where and prevents what ?
it is located on the Mitochondrial membrane and prevents the release of apoptosis inducing factor and used to make G6P for the PPP and Pyruvate Pathway
Warburg effect is basically
Increase in glycolysis
decrease in OP
increase in lactate production
To kill cancer we must
induce necrosis-----inhibit HK2 induce apoptosis-----release AIF decrease the pH in cell inhibit lactate release increase the ROS
3-bromopyruvate
modifies HK2 so it cannot bind VDAC
and AIF is released and necrosis insures
ATP stores depleted
HIF-1alpha
increases glycolysis and decreases OP
essential for metabolic changes for cancer
Cancer in summary
Hexokinase II and pyruavte kinase M2 up regulated
OP decreased (PDH unregulated to keep pyruvate out out of MIT)
the non-oxidative part of PPP increase due to TKL1 and PKM2
Glutamine upregulated
more ROS generated
fatty acid syn, protein syn upreglated
