GKA deel 1 college 12

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  • GK 2009 a.a.m.thomas@uu.nl
  • GK 2009 a.a.m.thomas@uu.nl
  • GKA deel 1 college 12

    1. 2. Death and methylation Jones, Nature 409, 2001, 141-144 <ul><li>Melanoma ontsnapt aan chemotherapie, p53 intact! </li></ul><ul><li>APAF-1 geïnactiveerd door methylering </li></ul><ul><li>= ‘epigenetic gene silencing’ </li></ul>GK '09
    2. 3. Death and methylation Jones, Nature 409, 2001, 141-144 <ul><li>Melanoma ontsnapt aan chemotherapie, p53 intact! </li></ul><ul><li>APAF-1 geïnactiveerd door methylering </li></ul><ul><li>= ‘epigenetic gene silencing’ </li></ul>GK '09
    3. 4. From bench to clinic with apoptosis agents Nicholson, Nature 407, 2000, 810-816 <ul><li>Artikel gekozen vanwege mechanisme apoptose </li></ul><ul><li>Apoptose mogelijk gevoelig voor medicijnen </li></ul><ul><li>Ideale medicijn: </li></ul><ul><ul><li>Klein </li></ul></ul><ul><ul><li>Anti-sense Bcl2 </li></ul></ul><ul><ul><li>Weefsel-, of cel-specifiek </li></ul></ul><ul><li>Test: transplantatie humane tumor in SCID of naakte muis </li></ul>GK '09
    4. 5. Antagonism of Bcl2 members Nicholson, Nature 407, 2000, 810-816 <ul><li>Kanker door onvoldoende apoptose </li></ul><ul><li>Bcl2 overexpressie  </li></ul><ul><ul><li>Anti-sense Bcl2 </li></ul></ul><ul><ul><ul><li>Thio 5’-TCT CCC AGC GTG CGC CAT-3’ </li></ul></ul></ul>GK '09
    5. 6. TRAIL pathway Nicholson, Nature 407, 2000, 810-816 <ul><li>TRAIL induceert apoptose </li></ul><ul><ul><li>Inductie TRAIL </li></ul></ul><ul><ul><ul><li>T NF- r elated a poptosis i nducing l igand </li></ul></ul></ul><ul><li>c-FLIP </li></ul><ul><ul><li>Anti-sense c-FLIP induceert apoptose </li></ul></ul><ul><ul><li>Pseudo-caspase </li></ul></ul><ul><ul><li>Decoy </li></ul></ul><ul><ul><li>Inhibitor of apoptosis =IAP </li></ul></ul><ul><li>Toch afhankelijk van p53? </li></ul><ul><ul><li>p53 Tc-factor van TRAIL-receptor </li></ul></ul>GK '09
    6. 7. Two major apoptosis pathways Hengartner Nature 407, 2000 <ul><li>Initiator: caspase 8 or 9 </li></ul><ul><li>CD95=Fas </li></ul><ul><li>In- and extrinsic activation </li></ul><ul><ul><li>Coupled via Bid! </li></ul></ul><ul><li>IAP: inhibitor of apoptosis </li></ul><ul><li>DIABLO: direct IAP-binding protein with low pI </li></ul><ul><li>SMAC: 2 nd mitochondria-derived activator of A </li></ul><ul><li>Role p53: induction Bax </li></ul>GK '09
    7. 8. TRAIL pathway Nicholson, Nature 407, 2000, 810-816 <ul><li>TRAIL induceert apoptose </li></ul><ul><ul><li>Inductie TRAIL </li></ul></ul><ul><ul><ul><li>T NF- r elated a poptosis i nducing l igand </li></ul></ul></ul><ul><li>c-FLIP </li></ul><ul><ul><li>Anti-sense c-FLIP induceert apoptose </li></ul></ul><ul><ul><li>Pseudo-caspase </li></ul></ul><ul><ul><li>Decoy </li></ul></ul><ul><ul><li>Inhibitor of apoptosis =IAP </li></ul></ul><ul><li>Toch afhankelijk van p53? </li></ul><ul><ul><li>p53 Tc-factor van TRAIL-receptor </li></ul></ul>GK '09
    8. 9. TRAIL pathway as inducers of apoptosis Nicholson, Nature 407, 2000, 810-816 <ul><li>CD95=Fas </li></ul><ul><ul><li>TNF-familie </li></ul></ul><ul><ul><li>p53-, Bcl2-onafhankelijke route </li></ul></ul><ul><li>Blauw: TNF trimeer </li></ul><ul><li>Grijs-geel: receptor trimeer </li></ul>GK '09
    9. 10. Caspases as therapeutic targets Nicholson, Nature 407, 2000, 810-816 GK '09 Tetrameer, Remmer is paars
    10. 11. Caspase inhibitor bij niet-tumorziekten Nicholson, Nature 407, 2000, 810-816 <ul><li>P1= Asp, D </li></ul><ul><li>zVAD= peptide-achtige remmer: paars </li></ul><ul><ul><li>Peptoide </li></ul></ul><ul><ul><li>Benzyloxy (=z)-VAD-fluormethylketon </li></ul></ul><ul><ul><li>Blokt actieve site </li></ul></ul><ul><li>Geel is niet-peptide remmer </li></ul><ul><li>Nuttig bij sommige hersenziekten </li></ul>GK '09 =================

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