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MCB2 Block 1 Cancer
N/A
156
Biochemistry
Graduate
05/13/2012

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Term
Aflatoxin B1
Definition
mold on peanuts in china, CYP450 converts it into a reactive epoxide so it intercalates inbetween DNA and forms adducts -->damage-->cancer
Term
Benzo-a-pyrene
Definition
In tobacco smoke and coal tar. Forms DNA adduct (covalent bond so can't replicate)
Term
Viral sarcoma
Definition
v-scr is a retrovirus. Acts as on oncogene
Term
Ret (Oncogene) (RTK)
Definition
GOF: multiple endocrine adenomatosis 2. Ret GOF --> overexpression of Cyclin D and E pushing cell through G1-S phase checkpoint; loss of fxn --> Hirschprung's
Term
Myc (Oncogene) (TF)
Definition
GOF: Burkitt lymphoma. Myc GOF --> overexpression of Cyclin D and E pushing cell through G1-S phase checkpoint. Activated in other cancers as wel.
Term
Met (Oncogene) (GF)
Definition
GOF: Hereditary papillary renal carcinoma. Met GOF --> overexpression of Cyclin D and E pushing cell through G1-S phase checkpoint; MET involved in embryonic development & wound healing (normally only stem cells express MET)
Term
fos/Jun (Oncogene) (TF)
Definition
Increased cell proliferation
Term
RTK
Definition
Receptor Tyrosine Kinase, ie; GFRs & insulinR. Activated by dimerisation: Ligand induced activation
3 major signal transduction pathways: 1. PLC: Breaks down membrane inositol phosphates to 2nd messengers; IP3 --> Ca2+ (released from ER) --> activation PKC and DAG --> activation PKC --> activation TFs 2. PI3K (Phosphatidyl-inositol 3-kinase): Phosphorylates membrane phospholipid --> Activation PKB --> inhibition apoptosis (survival)
3. MapK pathway
Term
PML-RARa (Oncogene) (TF + retinoic acid receptor)
Definition
GOF: Acute Promyelocytic Leukemia. (retinoic acid receptor alpha) = nuclear receptor & transcription factor. Normally activates transcription. Fusion is a repressor -->turn off myeloid differentiation and promote prolonged proliferation
Term
BCR-ABL (Oncogene) (TK)
Definition
GOF: Chronic myeogenous leukemia. RTK --> cell proliferation
Term
EWS-FLI1 (Oncogene) (TF)
Definition
GOF: Ewing Sarcoma. FLI1 is a TF
Term
N-MYC (Oncogene) (TF)
Definition
GOF: Neuroblastoma; double minutes, HSR
Term
Rb (Tumor Suppressor) (Phosphoprotein)
Definition
Retinoblastoma: if rb mutated, constitutive e2f activation. Loss of Rb = increase in miRNA, forms complex w mRNA and is degraded. When hypophosphorylated, it sequesters E2f, phosphorylated it is inactive and unbound to E2F; gatekeeper
Term
p53 ((Tumor Suppressor) (Phosphoprotein)
Definition
most comon genetic alteration in cancer. Normally involved in apoptosis, DNA repair, and stopping of cell cycle; gatekeeper
Term
Nf1 (Tumor Suppressor) (RasGAP)
Definition
Mutation leads to active Ras; gatekeeper
Term
BRCA1/BRCA2 (Tumor Suppressor) (MMR gene)
Definition
BRCA1
Female breast & ovarian cancer
BRCA2
Female breast & ovarian cancer
Male breast cancer (10-20% cases); Cellular response to dsDNA breaks
Term
APC (Tumor Suppressor) (Ser/Threonine kinase)
Definition
Familial polyposis coli (FAP): phosphorylates B-catenin sending for destruction; Apc negatively controls b-catenin. At bottom of crypts Apc is not expressed and b-catenin is high due to Wnt signalling. As cells migrate up, Apc is increasingly expressed and in the absence of WNT, b-catenin is degraded.
Term
B-catenin (TF)
Definition
if complexed bound to cadherin -->catenins-->actin. If free in cytoplasm (dephosphorylated) is a nuclear TF: cell proliferation (activate myc, transcription of cyclin D etc)
Term
Wnt (GF)
Definition
Signal that activates Frizzled receptor
Term
Frizzled (Receptor)
Definition
Activated by Wnt, this activates Disheveled by phosphorylating it
Term
Disheveled (Phosphatase)
Definition
Disheveled inhibits GSK-3b / Axin / APC complex via dephosphorylating B catenin within complex
Term
GSK/Axin/APC complex
Definition
Normally after synthesis b-catenin forms a multicomplex with Apc (adenomatous polyposis coli), axin & GSK3b. The complex phosphorylates b-catenin which tags it for ubiquitination.
Term
MLH1/MSH2 (Tumor Suppressor) (DNA repair genes)
Definition
caretaker proteins: mutation leads to HNPCC
Term
TGFβ receptor II (Tumor Suppressor)
Definition
Normalling involved in growth inhibitory signalling pathway - mutation occurs SECONDARY to repeat instability; uses Smad4 with phosphorylated RSMAD to activate p15/16 and cause apoptosis
Term
RER+ (MMR gene)
Definition
replication error positive phenotype (mutation in MLH1, MSH2 etc leads to microsatellite instability)
Term
SMAD4 (SMAD2/3) (Tumor Suppressor) (ser/thr kinase*)
Definition
signals downstream TGFB, part of growth inhibitory signalling cascae (p15/16)
Term
PTEN (Tumor Suppressor) (phosphatase)
Definition
cell cycle arrest + apoptosis. AKT (PKB) normally upregulates bcl2 antiapoptosis factor --> cell proliferation. PTEN removes phosphate from AKT (pkB) so it doesn't activate, therefore if mutated --> (cell proliferation). Found in prostate and breast cancers
Term
WT-1 (Tumor Suppressor)
Definition
Hereditary and sporadic Wilms tumor = pediatric kidney cancer. Involved in renal differentiation regulation: regulates the mesenchymal to epithelial transition) - loss of function in Wilms tumour
Term
TroVax (drug)
Definition
novel cancer vaccine; Delivers tumour-associated antigen, 5T4, using a virus vector. Induces anti-tumour immune response to the 5T4 tumor antigen. Used to treat colon cancer
Term
BLM (DNA Helicase)
Definition
Bloom syndrome: sun sensitive; caretaker
Term
WRN (DNA Helicase & exonuclease)
Definition
Werner syndrome: premature aging; caretaker
Term
FANCD2 (DNA repair)
Definition
Fanconi anaemia: bone marrow failure; caretaker
Term
Her2/EGFR2 (Oncogene) (Receptor)
Definition
Breast cancer: Signalling pathway is amplified at low levels of EGF (epidermal growth factor)
Term
Herceptin (Humanised mAB Trastuzumab) (drug)
Definition
monoclonal antibody against Her2 used in treatment of breast cancer (blocks her2 signalling); Activated EGFR complexes (either bound via ligand or mAb) are endocytosed via clathrin-coated pits. Monoubiquintination targets receptors to degradation in lysosome via multivesicular body
Term
Gefitinib (iressa) (drug)
Definition
Small molecule kinase inhibitors
Term
Erlotinib (tarceva) (drug)
Definition
Small molecule kinase inhibitors
Term
Gleevec (drug)
Definition
almost exclusively binds to BCR-ABL fusion protein in CML (aka Imatinib)
Term
Tamoxifen (drug)
Definition
Oestrogen receptor antagonists
Term
PSA (Oncogene) (GF)
Definition
Serum marker of overactive AR signalling
Term
Androgen ablation
Definition
Androgen receptor antagonists (flutamide, bicalutamide) = main therapeutic intervention for the treatment of hormone-sensitive prostate cancer
Term
MPF = M cyclin-cdk (cyclin B)
Definition
mitotic cyclin: allowing cell to enter M phase
Term
Cyclin D
Definition
G1 cyclin: binds to CDK 4/6
Term
Cyclin E
Definition
G1-S phase cyclin: binds to CDK2
Term
GADD45 (DNA repair)
Definition
promoted by p53 activation; caretaker
Term
INK4 (Tumor Suppressor)
Definition
inhibitors of kinase 4) family bind & inhibit only cyclin D-Cdk4/6 complexes: restriction point halt: e.g. p15, p16
Term
CIP (Tumor Suppressor)
Definition
(Cdk inhibitory protein) family bind inhibit remaining cyclin -Cdk complexes: e.g. p21 (CIP21)
Term
p16 (Tumor Suppressor)
Definition
normally inhibits Cyclin D-Cdk4/6; pRb not phosphorylated. pRb remains bound to E2F, no E2F activity. In proliferating cells, p16 inhibition removed, cyclin-cdk activity enabled, pRB phosphorylated, releases E2F
Term
p21 (Tumor Suppressor)
Definition
A CIP that blocks parts of the cell cycle. DNA damage strongly induces p21
Term
FAS/BAX (Tumor Suppressor) (Pro-apoptosis)
Definition
promoted by p53 activation; caretaker
Term
p14 Arf (Tumor Suppressor)
Definition
sequesters MDM2 which degrades p53, allows p53 to trigger cell cycle arrest in response to increased levels of E2F
Term
MDM2(Oncogene)
Definition
binds p53 in the nucleus and ubiquitinates it and sends it to the cytosol for destruction in proteosomes. Prevents p53 from acting as a checkpoint; p53 phosphorylation blocks Mdm2 binding, p53 accumulates, stimulates transcription of p21
Term
E6 (Oncogene) (HPV - oncoprotein)
Definition
degrades p53 through ubiquitin-degradation pathway
Term
E7 (oncogene) (HPV - oncoprotein)
Definition
oncoprotein binds, inhibits Rb
Term
Cyclin B/MPF/ Mcyclin
Definition
promotoes G2-->M checkpoint, phosphorylates nuclear envelope, requires CDK1. M-cyclin/Cdk1 complex activation leads to nuclear envelope breakdown, chromosome condensation and bipolar spindle assembly
Term
CAK (kinase)
Definition
CDK activating kinase
Term
Wee (kinase)
Definition
CDK inhibitory kinase, adds an inactivating phosphate
Term
cdc25 (phosphatase)
Definition
phosphatase that removes wee1 inactivating phosphate
Term
APC/C (ubiquitin ligase)
Definition
Anaphase-promoting complex (APC/C) initiates sister-chromatid separation at spindle-attachment checkpoint. Anaphase-promoting complex is a ubiquitin ligase that targets cyclin B and other mitotic regulators to proteosome
Term
Mad2
Definition
Kinetochore sensor allows APC/C activation
Term
ATM
Definition
Activated from DNA damage; activates BRCA1/2 which activates p53. Phosphorylates p53 releasing it from MDM2
Term
Interphase
Definition
Chromosome duplication and choesion, centrosome duplication
Term
Prophase
Definition
Breakdown of interphase microtubule dispay an its replacement by mitotic asters. Mitotic aster separation, chromosome condensation
Term
Prometaphase
Definition
Nuclear envelope breakdown, chromosomes captured, bi-oriented and brought to the spindle equator
Term
Metaphase
Definition
Chromosomes aligned at the metaphase plate
Term
Anaphase
Definition
APC/C activated and cohesions degraded. Anaphase A: Chromosome movement to poles B: spindle pole separation
Term
Telophase
Definition
Nuclear envelope reassemby. Assembly of contractile ring
Term
Cytokinesis
Definition
Reformation of interphase microtubule array, contractile ring forms cleavage furrow
Term
GP1b (integrin)
Definition
adhesion of platelets to subendothelial layers: binding of GP1b to collagen via Von Willebrand factor
Term
GPIIb/GPIIIa (integrin)
Definition
integrins on the platelet membrane that bind to fibrinogen
Term
Plavix (drug)
Definition
new anti-thrombotic agent that interferes with the GPIIb/GPIIIA/fibrinogen mediated platelet aggregation
Term
Dense bodies
Definition
Structure in platelets that release granules: ADP (platelet activator) and serotonin (constriction)
Term
Alpha granules
Definition
Release from platelets: include Von Willebrand factor - promotes platelet adhesion to collagen, and fibrinogen - platelet aggregation
Term
Thromboxanes
Definition
potent platelet activator; phospholipase A2 becomes active following platelet activation. From arachidonic acid liberated from membrane proteins thromboxane A2 is produced via intermediary prostaglandins; One of the key enzymes in this pathway is cyclooxygenase (CO) which is the target of non-steroidal anti-inflammatory drugs such as aspirin.
Term
vWF
Definition
von Willebrand factor (vWF) is complex multimeric adhesive glycoprotein synthesized exclusively in vascular endothelial cells and in megakaryocytes. VWF polypeptide has complex domain structure involving binding sites for Platelet Glycoprotein GP1b, for Collagen, and for Factor VIII; adhesion of platelets to the injured vessel wall
Term
prothrombin
Definition
Factor II - cleaved to make thrombin: cleaved by factor Xa in the presence of factor Va
Term
thrombin
Definition
cleaves fibrinogen to fibrin, helping to form small aggregates
Term
Factor XIIIa
Definition
forms covalent peptide bonds between aa's in fibrin, crosslinking/adding stability to fibrin clots
Term
Tissue factor (TF)
Definition
cell surface protein that when is exposed to plasma, will induce blood clotting. Factor Viia is not active without TF
Term
Thrombomodulin
Definition
Thrombin, bound to thrombomodulin on the endothelial cell surface, activates protein C. Activated protein C (APC) in complex with protein S, binds to the platelet membrane, and the activated complex destroys Factors Va and VIIIa, thereby inhibiting the coagulation cascade
Term
Factor VII
Definition
activated in trauma, cleaved to VIIa and requires TF, catalyzes factor X cleavage
Term
Factor VIII
Definition
VIIIa catalyzes factor X cleavage to Xa
Term
Factor IX
Definition
Requires factor VIII to help cleave factor X
Term
Factor X
Definition
Requires factor V to catalyze prothrombin to thrombin
Term
Antithrombin
Definition
Anticoagulant: a serpin (serine protease inhibitor) irreversibly inactives serine proteases mainly factor Xa and thrombin
Term
Heparin
Definition
Ability of antithrombin to inactivate Xa or thrombin is stimulated by heparin: The rate of inactivation is stimulated 17000 fold for factor Xa and 9000 fold for thrombin
Term
Plasmin
Definition
Serine protease that degrades fibrin clots; "Plasminogen is converted to plasmin by two serine proteases: tissue-type plasminogen activator (tPA)
urinary-type plasminogen activator (uPA; urokinase)"
Term
Warfarin
Definition
Coumarin drug that antagonizes Vit K Depresses vitamin K-dependent carboxylation of several clotting factors (prothrombin, protein C, protein S, and factors VII, IX and X); Coumarin drugs are being replaced by direct inhibitors of factor Xa or of thrombin
Term
Thrombolytic drugs
Definition
Activate plasminogen: tPA (Activase®)
uPA (Abbokinase®)
streptokinase (Streptase®)
Term
Telomerase
Definition
Protein-RNA complex containing (reverse transcriptase) that renews telomeres using RNA templates
Term
TERT
Definition
Part of telomerase that is reverse transcriptase
Term
TERC
Definition
Part of telomerase that is RNA template
Term
Replicative senescence
Definition
Without telomerase → progressive telomere shortening. Eventually chromosome ends will be damaged → G0 (no cell dividing)
Term
FasR
Definition
Death Receptor binds to FasL, leads to activation of caspase-8
Term
TNF
Definition
Receptor that binds to TNF-a, leads to activation of caspase-8
Term
Caspase-8
Definition
Initiates a cascade of caspases in extrinsic pathway
Term
FADD (Adapter protein)
Definition
bind intracellular region of aggregated Fas receptors, aggregating procaspase-8
Term
Cyt-c
Definition
Released by mitochondria in intrinsic pathway of apoptosis: Binds to Apaf-1 which oligomerizes into the apoptososme
Term
Apaf-1
Definition
Apoptosis protease-activating factor 1
Term
Apoptosome
Definition
adaptor for pro-caspase-9: composed of Apaf-1 and cytochrome C
Term
Pro-caspase-9
Definition
aggregates, activates, initiates caspase zymogen cascade
Term
Caspases
Definition
cysteine proteases. The term caspases (cysteine-dependent aspartate-specific proteases). Synthesized as zymogens (“procaspases”) that are activated by caspase-mediated cleavage. Extrinsic/intrinsic pathways converge on caspases 3,6,7
Term
CAD
Definition
Caspase-induced Dnase Endonuclease: activated by caspase-3 which cleaves CAD’s inhibitory protein. Allows active CAD to go to nucleus & fragment DNA.
Term
Bcl-2 (oncogene)
Definition
linked to an immunoglobulin locus by t(14:18) in follicular lymphoma. oncogene that inhibits cell death rather than promoting proliferation
Term
Bcl2/Bcl-Xl (oncogene)
Definition
Anti-apoptotic: block release of cytochrome c & Smac/DIABLO out of mitochondria
Term
Smac/DIABLO (Tumor suppressor)
Definition
inhibits IAP (“inhibitor of apoptosis”) proteins, allows caspase activation to proceed
Term
Bid
Definition
links the extrinsic to intrinsic apoptotic pathways by binding bcl's freeing bax/bak to make homodimer pores in mitochondria
Term
Caspase-3
Definition
Both extrinsic and intrinsic pathways converge on caspase 3,6,7
Term
Hypoxia
Definition
a condition in which there is a need for oxygen, occurs in center of tumor
Term
HIF
Definition
hypoxia induces HIF (hypoxia inducing factor) which in turn induces VEGF
Term
VEGF (TF)
Definition
binds VEGFR (RTK) on nearby endothelial cells → Chemotaxis: migration towards angiogenic stimulus: endothelial cells proliferate, differentiate, secrete proteases &
migrate (integrins) → ↑ permeability → ↑ migration, ↑ nutrients & plasma proteins
Term
MMPs
Definition
Matrix metalloproteinases (MMPs)
Collagenases: required for angiogenesis
Term
TIMPs
Definition
Proteinase inhibitors: MMP:TIMP unbalanced at invading edge of tumours
Term
Normoxia
Definition
(normal oxygen tension) proline hydroxylase adds OH to HIF-1, requires O2. HIF-1-OH binds pVHL (tsg), triggers ubiquitination → degradation
Term
Bevacizumab
Definition
Inactivates VEGF
Term
Trastuzumab
Definition
Her2
Term
Cetuximab
Definition
EGFR
Term
Thrombospondin
Definition
Will cause new & old endothelial cells to secrete FasL. → FasL-FasR = apoptosis. Will only occur on new vasculature
Term
Endostatin
Definition
Stabilises new BV wall. Anchors endothelial tubes to basement membrane and between endothelial cells  vascular maturation
Inhibits new vessel sprouting
Term
Tarceva & Iressa
Definition
EGFR Tki
Term
tPA, uPA (serine protease)
Definition
Tissue plasminogen activator which catalyzes plasminogen --> plasmin. Degradation of ECM
Term
AMF (motility factor)
Definition
Chemokine involved in tumour motility it upregulates Rho (migration), MAPK (proliferation), PI3k (survival), and VEGF (angiogenesis)
Term
HGF (motility factor)
Definition
Chemokine involved in tumour motility it upregulates HGFR which in turn upregulates Rho (migration), MAPK (proliferation), PI3k (survival), angiogenesis, B-catenin/Wnt, protease
Term
Intravasation
Definition
When a primary tumor invades the basal membrane and enters blood vessels: caused by HIF --> increase VEGF --> endocytosis of VE-cadherin
--> increase in vascular permeability
Term
CXCR4
Definition
Chemokine regulation of breast cancer Metastases: CXCR4 binds CXCL12 and CCR7 binds CCL21
Term
Invadopodia
Definition
Part of extravastion of a tumour: it is the integrin interaction with endothelial BM and with proteases
Term
PARP (Anti-Cell Cycle) (DNA repair)
Definition
Poly ADP-ribose polymerase fixes ssDNA. Cancer w loss of BRCA1/2 repair are sensitive to PARP inhibitors --> so turn off all repair in hopes cells will die
Term
Paclitaxel (Anti-Cell Cycle)
Definition
binds and stabilizes microtubules so NO disassembly (prevents M phase)
Term
Vinblastine (Anti-Cell Cycle)
Definition
Binds tubulin subunits and prevents polymerization (prevents Mphase)
Term
Vincristine (Anti-Cell Cycle)
Definition
Binds tubulin subunits and prevents polymerization (prevents Mphase)
Term
Doxorubicin (Anti-Cell Cycle)
Definition
Topoisomerase II Inhibitor: Too much damage, cant repair will initiate cell death. Low dose of doxorubicin induces mitotic catastrophe (cell death) (another ex of this drug: Etoposide)
Term
5-Fluorouracil
(5-fu) (Anti-Cell Cycle)
Definition
S-phase inhibitor: antimetabolite - pyrimidine analogues structurally related to naturally occurring compounds. Interfere with production of nucleic acids. Inhibit enzymes of nucleoside triphosphate synthesis.
Term
Methotrexate (Anti-Cell Cycle)
Definition
S-phase inhibitor: Folic Acid Analogues, blocks DNA synthesis
Term
Cyclophosphamide (Anti-Cell Cycle)
Definition
G1-->S Phase Inhibitors: Alkylating agent. Abnormal base-pairing with thymine --> mutation. Also excision of alkylated guanine residues (depurination) --> strand breakage. Cross-linking may also occur, preventing strand separation
Term
Platinum Complexes (Anti-Cell Cycle)
Definition
G1-->S Phase Inhibitors: Intercalating agent. Reactive- form complexes between guanine nucleotides --> mutation, DNA cross-linking, base excision & double strand breaks
Term
Mitotic Catastrophe
Definition
Lack G2-->M Checkpoint control → “Mitotic catastrophe” = aberrant chromosome segregation triggers p53-independent apoptosis → cell death during mitosis; "Cells that do not undergo “mitotic catastrophe” aneuploidy, polyploidy,
chromosome aberrations → oncogenesis / cell death. (doxorubicin causes mitotic catastrophe)"
Term
Adenoviral p53 gene therapy
Definition
Pro-Apoptosis Cancer Strategy via a viral vector
Term
Oblimersen, Genasense
Definition
Pro-Apoptosis Cancer Strategy anti-sense strategy for Bcl-2
Term
Mdr1 amplification
Definition
ABC transporter superfamily; prevents intracellular accumulation of cytotoxic drugs. Allows cell to survive (pump out drug)
Term
Cyclin D-Cdk4
Definition
Mid-G1
Made at start of G1
REQUIRED FOR PASSAGE THROUGH RESTRICTION POINT
Term
Cyclin E-Cdk2
Definition
Late G1-->S
DNA damage induced pathways target degradation of Cyclin D, then Cyclin E to stop cell cycle progression
Term
Cyclin A-Cdk2
Definition
S phase
Term
Cyclin B-Cdk1
Definition
G2-->M
Term
Cyclin A-Cdk1
Definition
M phase
Term
Platelet secretions from dense bodies
Definition
Adenosine diphosphate (platelet activator)
Serotonin (vasoconstrictor)
Term
Platelet secretions from alpha granules
Definition
von Willebrand factor (promotes platelet adhesion to collagen)
Fibrinogen (promotes platelet aggregation)
Term
Thromboxane A2
Definition
Potent platelet activator produced from arachidonic acid
Key enzyme - cyclo-oxygenase (CO) = target for asprin and NSAIDs
Term
von Willebrand factor (vWF)
Definition
Synthesized by megakaryocytes, vascular endothelial cells
Binding sites for GP1b, collagen, factor 8
Essentail for formation of clot (involved in adhestion of platelets to injured vessel wall)
Stabilized factor 8 in circulation (forms complex)
Present in subendothelial matrix
Term
Activation serine proteases
Definition
Prothrombin
Factor 7 (receptor and cofactor = TF)
Factor 9 (cofactor = factor 8)
Factor 10 (cofactor = factor 5)
Term
Inhibition serine proteases
Definition
Protein C (receptor = thrombomodulin, cofactor = protein S)
Term
Warfarin
Definition
Oral anticoagulant
Antagonizes vitamin K
Term
Angiostatin
Definition
Induces apoptosis
Term
Thrombospondin
Definition
Induces FasL secretion
Term
Endostatin
Definition
Stabilizes new blood vessel wall; inhibits new blood vessels from sprouting
Term
AMF (and HGF)
Definition
Autocrine motility factor- activates Rho GTPase
Term
Chemokine regulation of breast cancer metastasis:
CXCR4 binds:
Definition
CXCL12
Term
Chemokine regulation of breast cancer metastasis:
CCR7 binds:
Definition
CCL21
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