Term
|
Definition
| mold on peanuts in china, CYP450 converts it into a reactive epoxide so it intercalates inbetween DNA and forms adducts -->damage-->cancer |
|
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Term
|
Definition
| In tobacco smoke and coal tar. Forms DNA adduct (covalent bond so can't replicate) |
|
|
Term
|
Definition
| v-scr is a retrovirus. Acts as on oncogene |
|
|
Term
|
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 |
|
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Term
|
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. |
|
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Term
|
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) |
|
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Term
|
Definition
| Increased cell proliferation |
|
|
Term
|
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
|
Definition
| GOF: Chronic myeogenous leukemia. RTK --> cell proliferation |
|
|
Term
|
Definition
| GOF: Ewing Sarcoma. FLI1 is a TF |
|
|
Term
|
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. |
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|
Term
|
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
|
Definition
| Signal that activates Frizzled receptor |
|
|
Term
|
Definition
| Activated by Wnt, this activates Disheveled by phosphorylating it |
|
|
Term
|
Definition
| Disheveled inhibits GSK-3b / Axin / APC complex via dephosphorylating B catenin within complex |
|
|
Term
|
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
|
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
|
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
|
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
|
Definition
| Bloom syndrome: sun sensitive; caretaker |
|
|
Term
| WRN (DNA Helicase & exonuclease) |
|
Definition
| Werner syndrome: premature aging; caretaker |
|
|
Term
|
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
|
Definition
| almost exclusively binds to BCR-ABL fusion protein in CML (aka Imatinib) |
|
|
Term
|
Definition
| Oestrogen receptor antagonists |
|
|
Term
|
Definition
| Serum marker of overactive AR signalling |
|
|
Term
|
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
|
Definition
| G1 cyclin: binds to CDK 4/6 |
|
|
Term
|
Definition
| G1-S phase cyclin: binds to CDK2 |
|
|
Term
|
Definition
| promoted by p53 activation; caretaker |
|
|
Term
|
Definition
| inhibitors of kinase 4) family bind & inhibit only cyclin D-Cdk4/6 complexes: restriction point halt: e.g. p15, p16 |
|
|
Term
|
Definition
| (Cdk inhibitory protein) family bind inhibit remaining cyclin -Cdk complexes: e.g. p21 (CIP21) |
|
|
Term
|
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
|
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
|
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
|
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
|
Definition
|
|
Term
|
Definition
| CDK inhibitory kinase, adds an inactivating phosphate |
|
|
Term
|
Definition
| phosphatase that removes wee1 inactivating phosphate |
|
|
Term
|
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
|
Definition
| Kinetochore sensor allows APC/C activation |
|
|
Term
|
Definition
| Activated from DNA damage; activates BRCA1/2 which activates p53. Phosphorylates p53 releasing it from MDM2 |
|
|
Term
|
Definition
| Chromosome duplication and choesion, centrosome duplication |
|
|
Term
|
Definition
| Breakdown of interphase microtubule dispay an its replacement by mitotic asters. Mitotic aster separation, chromosome condensation |
|
|
Term
|
Definition
| Nuclear envelope breakdown, chromosomes captured, bi-oriented and brought to the spindle equator |
|
|
Term
|
Definition
| Chromosomes aligned at the metaphase plate |
|
|
Term
|
Definition
| APC/C activated and cohesions degraded. Anaphase A: Chromosome movement to poles B: spindle pole separation |
|
|
Term
|
Definition
| Nuclear envelope reassemby. Assembly of contractile ring |
|
|
Term
|
Definition
| Reformation of interphase microtubule array, contractile ring forms cleavage furrow |
|
|
Term
|
Definition
| adhesion of platelets to subendothelial layers: binding of GP1b to collagen via Von Willebrand factor |
|
|
Term
|
Definition
| integrins on the platelet membrane that bind to fibrinogen |
|
|
Term
|
Definition
| new anti-thrombotic agent that interferes with the GPIIb/GPIIIA/fibrinogen mediated platelet aggregation |
|
|
Term
|
Definition
| Structure in platelets that release granules: ADP (platelet activator) and serotonin (constriction) |
|
|
Term
|
Definition
| Release from platelets: include Von Willebrand factor - promotes platelet adhesion to collagen, and fibrinogen - platelet aggregation |
|
|
Term
|
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
|
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
|
Definition
| Factor II - cleaved to make thrombin: cleaved by factor Xa in the presence of factor Va |
|
|
Term
|
Definition
| cleaves fibrinogen to fibrin, helping to form small aggregates |
|
|
Term
|
Definition
| forms covalent peptide bonds between aa's in fibrin, crosslinking/adding stability to fibrin clots |
|
|
Term
|
Definition
| cell surface protein that when is exposed to plasma, will induce blood clotting. Factor Viia is not active without TF |
|
|
Term
|
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
|
Definition
| activated in trauma, cleaved to VIIa and requires TF, catalyzes factor X cleavage |
|
|
Term
|
Definition
| VIIIa catalyzes factor X cleavage to Xa |
|
|
Term
|
Definition
| Requires factor VIII to help cleave factor X |
|
|
Term
|
Definition
| Requires factor V to catalyze prothrombin to thrombin |
|
|
Term
|
Definition
| Anticoagulant: a serpin (serine protease inhibitor) irreversibly inactives serine proteases mainly factor Xa and thrombin |
|
|
Term
|
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
|
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
|
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
|
Definition
Activate plasminogen: tPA (Activase®)
uPA (Abbokinase®)
streptokinase (Streptase®) |
|
|
Term
|
Definition
| Protein-RNA complex containing (reverse transcriptase) that renews telomeres using RNA templates |
|
|
Term
|
Definition
| Part of telomerase that is reverse transcriptase |
|
|
Term
|
Definition
| Part of telomerase that is RNA template |
|
|
Term
|
Definition
| Without telomerase → progressive telomere shortening. Eventually chromosome ends will be damaged → G0 (no cell dividing) |
|
|
Term
|
Definition
| Death Receptor binds to FasL, leads to activation of caspase-8 |
|
|
Term
|
Definition
| Receptor that binds to TNF-a, leads to activation of caspase-8 |
|
|
Term
|
Definition
| Initiates a cascade of caspases in extrinsic pathway |
|
|
Term
|
Definition
| bind intracellular region of aggregated Fas receptors, aggregating procaspase-8 |
|
|
Term
|
Definition
| Released by mitochondria in intrinsic pathway of apoptosis: Binds to Apaf-1 which oligomerizes into the apoptososme |
|
|
Term
|
Definition
| Apoptosis protease-activating factor 1 |
|
|
Term
|
Definition
| adaptor for pro-caspase-9: composed of Apaf-1 and cytochrome C |
|
|
Term
|
Definition
| aggregates, activates, initiates caspase zymogen cascade |
|
|
Term
|
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
|
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
|
Definition
| linked to an immunoglobulin locus by t(14:18) in follicular lymphoma. oncogene that inhibits cell death rather than promoting proliferation |
|
|
Term
|
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
|
Definition
| links the extrinsic to intrinsic apoptotic pathways by binding bcl's freeing bax/bak to make homodimer pores in mitochondria |
|
|
Term
|
Definition
| Both extrinsic and intrinsic pathways converge on caspase 3,6,7 |
|
|
Term
|
Definition
| a condition in which there is a need for oxygen, occurs in center of tumor |
|
|
Term
|
Definition
| hypoxia induces HIF (hypoxia inducing factor) which in turn induces VEGF |
|
|
Term
|
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
|
Definition
Matrix metalloproteinases (MMPs)
Collagenases: required for angiogenesis |
|
|
Term
|
Definition
| Proteinase inhibitors: MMP:TIMP unbalanced at invading edge of tumours |
|
|
Term
|
Definition
| (normal oxygen tension) proline hydroxylase adds OH to HIF-1, requires O2. HIF-1-OH binds pVHL (tsg), triggers ubiquitination → degradation |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| Will cause new & old endothelial cells to secrete FasL. → FasL-FasR = apoptosis. Will only occur on new vasculature |
|
|
Term
|
Definition
Stabilises new BV wall. Anchors endothelial tubes to basement membrane and between endothelial cells vascular maturation
Inhibits new vessel sprouting |
|
|
Term
|
Definition
|
|
Term
| tPA, uPA (serine protease) |
|
Definition
| Tissue plasminogen activator which catalyzes plasminogen --> plasmin. Degradation of ECM |
|
|
Term
|
Definition
| Chemokine involved in tumour motility it upregulates Rho (migration), MAPK (proliferation), PI3k (survival), and VEGF (angiogenesis) |
|
|
Term
|
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
|
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
|
Definition
| Chemokine regulation of breast cancer Metastases: CXCR4 binds CXCL12 and CCR7 binds CCL21 |
|
|
Term
|
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
|
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
|
Definition
| Pro-Apoptosis Cancer Strategy anti-sense strategy for Bcl-2 |
|
|
Term
|
Definition
| ABC transporter superfamily; prevents intracellular accumulation of cytotoxic drugs. Allows cell to survive (pump out drug) |
|
|
Term
|
Definition
Mid-G1
Made at start of G1
REQUIRED FOR PASSAGE THROUGH RESTRICTION POINT |
|
|
Term
|
Definition
Late G1-->S
DNA damage induced pathways target degradation of Cyclin D, then Cyclin E to stop cell cycle progression |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
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
|
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
|
Definition
Oral anticoagulant
Antagonizes vitamin K |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| Stabilizes new blood vessel wall; inhibits new blood vessels from sprouting |
|
|
Term
|
Definition
| Autocrine motility factor- activates Rho GTPase |
|
|
Term
Chemokine regulation of breast cancer metastasis:
CXCR4 binds: |
|
Definition
|
|
Term
Chemokine regulation of breast cancer metastasis:
CCR7 binds: |
|
Definition
|
|
