apoptosis: mechanisms (day 1) - columbia · pdf fileapoptosis: mechanisms (day 1) ......
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Apoptosis: Mechanisms (Day 1)
• Historical Perspective• Serine-threonine kinases, survival signaling
downstream of PTEN/PI3K/Akt• Bcl-2 family members, potential usage of
BH3 domains as drug targets• Mitochondrial pathway, apoptogenic factors
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Apoptosis: Drug targets (Day 2)
• Caspases, apoptosome, inflammasome• TNFR, CD95/Fas, ApoL• TRAIL and decoy receptors• Bcl-2/xL: Antisense, inhibitors of protein-
protein interactions, SAR• Caspases: Why it did not work
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Historical Observations of Apoptosis in Development
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Historical Timeline of Apoptosis Research
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Cell Death(Apoptosis)
Proliferation
Differentiation
Cell Death is a Physiological Response of CellsTo Changes in the Extracellular Environment
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Cell Death(Apoptosis)
Tumor suppressor genes(e.g., p53, PTEN, Caspases)
Oncogenes(e.g., AKT, Bcl-2)
DrugsIrradiation
Stress
Endogenous Genes Modify Cell Death
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Mitochondria Conduct Apoptotic Signaling
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Cellular Receptors Transduce Extracellular Signals
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Cellular Receptors Initiate Intracellular Cascades
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PtdIns-Dependent Second Messengers FunctionIn Distinct Intracellular Pathways…
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… Depending on Distinct Regulatory DomainsOf Target Proteins
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PIP3-Dependent Cell Responses are Mediated byPTEN/PI3K/AKT
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Multiple Cell Functions are Mediated byPTEN/PI3K/AKT
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PTEN/PI3K/AKT Signal Transduction isEvolutionarily Conserved
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Loss of AKT Signaling Leads to Lifespan Extensionand Reduced Cell Size (=Smaller Organisms)
Yeast (sch9) Fly (Dakt) Mouse (Akt1,2,3)
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Decreased Akt Gene Function = Mini-Mice
Akt1 KO(~20% smaller)
Akt1 wtLittermate
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Increased Strength of AKT Signaling = Cancer
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AKT Regulates Distinct Downstream Substrates
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AKT: A BAD Kinase Makes Good
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Mitochondria = Pandora’s Box of Cell Death
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Bcl-2 Proteins as Conserved GatekeepersOf Mitochondrial Integrity
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Death Signals Inhibit the Anti-Apoptotic Bcl-2Family Member CED-9 in Lower Eukaryotes
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Conservation of a Common Death PathwayInvolving Bcl-2-Type Proteins
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Pro-Apoptotic Bcl-2 Family Members in MammalsComprise Functionally Distinct Sentinels…
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…That Sense Cellular Stress and are Activated byMultiple Mechanisms…
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…Including Cleavage by Cellular Proteases
BID (inactive) tBID (active)
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Bcl-2-Type Proteins are Characterized by the BH3Domain of Protein-Protein Interactions…
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…but Comprise a Family of Structurally andFunctionally Diverse Proteins
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Inhibition of Bcl-2/Bcl-xL Results in the Release of Apoptogenic Factors
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Bcl-2/Bcl-xL Retain Apoptogenic Proteins in theMitochondrial Intermembrane Space…
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…by Regulating Mitochondrial Channels andInhibiting Pore Formation by Bax/Bak
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Mitochondrial Breakdown Results from thePermeabilization, Rupture or Leakage of the
Outer Mitochondrial Membrane (OMM)
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Bcl-2/Bcl-xL as Drug Targets
• Antisense Oligonucleotides [e.g. Genta=G-3139 (5’-d(P-thio)TCT-CCC-AGC-GTG-CCC-CAT-3’)
• Natural Compounds (Antimycin A3 binds to the hydrophobic groove in Bcl-xL and inhibits protein-protein interactions)
• SAR by NMR = structure-activity relationships by nuclear magnetic resonance
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SAR-by-NMR Method: Screening for Small Moleculesand Improving their Affinities using Linkers and NMR
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Advantage over Conventional Library Methods:Fewer Compounds have to be Synthesized
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Sequence-Specific Proteases (Caspases) ExecuteApoptotic Disassembly of Cellular Protein
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Caspases Contain Similar Catalytic SubunitsAnd Distinct N-terminal Regulatory Domains
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Initiator Caspases (Caspase-8,9) are ActivatedAccording to the Forced-Proximity-Model…
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…Downstream of Death Signals (Caspase-8)Or Mitochondrial Damage (Caspase-9)
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Executioner Caspases (Caspase-3,6,7) FormStructural Heterodimers
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Executioner Caspases Require Processing by UpstreamProteases for Dimer Formation (=Activation)
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Caspase-9 Differs from Other Caspases byHaving Only a Single Active Site…
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…that is Formed by the Induced Complex Formation of Caspase-9 Molecules
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Apaf-1 Mediates the ATP/dATP- and Cytochrome c-Dependent Multimerization of Caspase-9
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Electron Microscopy Photographs of Apaf-1In Complex with dATP and Cytochrome c
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Apaf-1 Complexes (=Apoptosomes) Form PropellerStructures with Heptagonal Symmetry (=7-fold)
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Components of the Apoptosome are LocalizedIn Defined Parts of the Propeller Structure
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Caspase-9 Molecules are Localized to the HubAnd Form a Dome that is the Basis for the…
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…Formation of the ‘Evil Oreo’ of Apoptosis
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Caspase Activity is Determined with FluorogenicTetrapeptides Resembling Protease Cleavage Sites
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Systematical Permutations of Tetrapeptide SequencesReveal Synthetic Substrate Peptides…
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…With Increased Specificity for Selected CaspasesAnd Groups of Caspases…
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…That Form the Rational for the Generation ofPeptoid Caspase Inhibitors
Unfortunately: Limited Practical Use because ofHepatobiliar P1-Asp Transporter System (=Secretion)
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In Summary: Death Receptor Signals (Extrinsic)Induce Caspase-8 Activation while …
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…Cellular Stresses (Intrinsic) Cause MitochondrialDamage Leading to Caspase-9 Activation
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Other Caspases (Caspase-1,5) are Involved inInflammatory Cell Responses…
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…That Involve Multimolecular Complexes…
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G9600 TFF 2003
…And Lead to the Assembly of an Inflammasome
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G9600 TFF 2003
Extrinsic Cell Death Pathways Depend onDeath-Receptor Ligands such as TRAIL
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G9600 TFF 2003
CD95/Fas/Apo1 Caspase-8 Activation (=Death)
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G9600 TFF 2003
Apo2L/TRAIL Caspase-8 Activation (=Death)
Increased Sensitivity in Cancer Cells (Lack of Decoy Receptors)
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G9600 TFF 2003
κ
κ
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Apo3L/TNF Caspase-8 Activation (=Death)+ NF-κB Activation (=Survival)
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G9600 TFF 2003
Outlook: DNA Damage Responses
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G9600 TFF 2003
Outlook: Role of p53