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GKA deel 1 college 9 GKA deel 1 college 9 Presentation Transcript

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  • p53 Lu et al., (2009) Nature Rev Cancer 9: 758-762
  • Latest news on HIV vaccine trial RV 144 Rerks et al., (2009) New Engl J Med
    • Up till now, all trials ended without positive results
    • Thailand Phase III trial
      • ± 8000 received 4 x ALVAC-HIV, 2 x AIDSVAX
        • rgp120
      • ± 8000 received placebo
  • Latest news on HIV vaccine trial RV 144 Rerks et al., (2009) New Engl J Med
    • Up till now, all trials ended without positive results
    • Thailand Phase III trial
      • ± 8000 received 4 x ALVAC-HIV, 2 x AIDSVAX
        • rgp120
      • ± 8000 received placebo
  • Latest news on HIV vaccine trial RV 144 Rerks et al., (2009) New Engl J Med
    • Up till now, all trials ended without positive results
    • Thailand Phase III trial
      • ± 8000 received 4 x ALVAC-HIV, 2 x AIDSVAX
        • rgp120
      • ± 8000 received placebo
    • Good news?
    • Statistically just significant, but only third row.
    • No decrease in viral load
    • Copies of editorial available
  • The p53 network Vogelstein et al., Nature 2000, 408: 307-310
    • 3 manieren van p53 activatie = stabilisatie
    ATM kinase DNA- dependent kinase ATR kinase Casein kinase II p14 ARF p21 GADD45 14-3-3  Reprimo Fas Bax Reactive oxygen species TRAIL DNA breaks Oncogenes UV, stress Santra et al., (2009) Nature 459, 722-725 p21 p21Waf (Weinberg!)
  • Action of p53 Vogelstein
    • p53 is a transcription factor
    • N-terminus
      • mdm2 interaction
      • transactivation: transcription effect
    • C-terminus
      • blocks N-terminus
    Cancer cells do not arrest in G1 or G2 and replication of damaged DNA results in an increased risk of tumor formation due to accumulation of mutations Normal cells arrest in G1 or G2 to effect DNA repair mechanisms Cells cycles normally if repair of genes is succesful Apoptosis occurs if repair of genes is unsuccessful: prevents continuation of genetic defects and possible development of tumor cells Ionizing radiation effects DNA damage and induces p53 expression Evolutionary conserved Transactivation Oligomerisation Binding sites Mutation hotspots the p53 gene a gene The p53 tumor suppressor gene
  • Rol BRCA1 en 2 in DNA schade bron: Google/Internet....
  • Vogelstein: Domain structure of p53 Prives and Manley, Cell 107, 2001, 815-818
    • Fosforylation
      • Less mdm2 binding 
        • More p53
    • Acetylation
      • Activation for transcription
    • Methylation
      • Specific function unknown
    Sequestering of DNA-binding domain
  • Vogelstein: Domain structure of p53 Prives and Manley, Cell 107, 2001, 815-818
    • Fosforylation
      • Less mdm2 binding 
        • More p53
    • Acetylation
      • Activation for transcription
    • Methylation
      • Specific function unknown
    Sequestering of DNA-binding domain
  • Vogelstein: Domain structure of p53 Prives and Manley, Cell 107, 2001, 815-818
    • Fosforylation
      • Less mdm2 binding 
        • More p53
    • Acetylation
      • Activation for transcription
    • Methylation
      • Specific function unknown
        • Yet
    Sequestering of DNA-binding domain Jansson et al., 2008 Nature Cell Biology 10, 1431 – 1439, Arginine methylation regulates p53 response
  • mdm2 and p53 Vogelstein et al., Nature 408, 2000, 307-310
    • Structure of the mdm2 gene and protein
      • From: Iwakuma and Lozano, Mol. Cancer Res. 1, 2003, 993-1000
      • M ouse d ouble m inute
    NLS : nuclear localization signal NES : nuclear export signal Zn- and RING-finger: protein interaction domains
  • mdm2 and p53 Vogelstein et al., Nature 408, 2000, 307-310
    • Structure of the mdm2 gene and protein
      • From: Iwakuma and Lozano, Mol. Cancer Res. 1, 2003, 993-1000
      • M ouse d ouble m inute
    NLS : nuclear localization signal NES : nuclear export signal Zn- and RING-finger: protein interaction domains
  • p53 and p19 ARF From Moll and Petrenko, Mol. Cancer Res. 1, 2003, 1001-1008 ARF=human p14 ARF =mouse p19 ARF ARF binds mdm2 protein nucleolus
  • p53 and p19 ARF From Moll and Petrenko, Mol. Cancer Res. 1, 2003, 1001-1008 ARF=human p14 ARF =mouse p19 ARF ARF binds mdm2 protein nucleolus
    • p53 activation:
    • Phosphorylation
      • Stabilization
    • Acetylation
      • Conformation/ unfolding
    • Tetramerization
    • Localization
    • Methylation
  • The ARF-mdm2-p53 pathway Sherr, Nature Rev Cancer 2006, 6, 663-673
    • Oncogenes activate Tc of ARF gene
      • ARF: alternative reading frame (Ink4 locus)
    • p53 is transcription factor of mdm2-gene
    • Mdm2: degradation of p53
    • ARF holds mdm2 in nucleolus
    Oncogene activation, such as Myc, E2F, Ras, Bcr-Abl DNA damage ATM-ATR DNA damage Chk1-Chk2 X-ray, UV, genotoxic drugs, hypoxia ARF p53 Mdm2
  • Surfing the p53 network Vogelstein et al., Nature 2000, 408: 307-310 Lack of p53 function; p53 functions only in nucleus Breast, neuroblastoma Mislocalization of p53 to cytoplasm Failure to inhibit MDM2 and to control p53 degradation Breast, brain, lung, tumours in which p53 itself is not mutated Deletion of the p14 ARF gene Viral proteins bind and inactivate p53 Cervix, liver, lymphomas Viral infection Extra mdm2 stimulates degradation of p53 Sarcomas, brain Multiplication of the MDM2 gene Prevents formation of tetramers of p53 Occasional tumours at many different sites Deletion of carboxy-terminal domain Prevents p53 from binding DNA and to activate genes Colon, pancreas, lung, bladder, many others Amino acid mutation in DNA- binding domain Effect of inactivation Typical tumours Mechanism of p53 inactivation
  • Viral oncogenes and the p53 network Vogelstein et al., Nature 2000, 408: 307-310 p14 ARF protein MDM2 p53 Viral p53- inactivating proteins E2F1 E2F1 Rb Rb Viral Rb-binding proteins Polager &Ginsberg Nature Rev Cancer Oct 2009
  • Summary p53 Cancer: three birds with one stone Toledo & Bardot (2009): Nature 460, 466-467 DNA breaks ATM kinase DNA- dependent kinase ATR kinase p14 ARF UV, stress Oncogenes p53 stabilisation Block angiogenesis
  • Summary p53 Cancer: three birds with one stone Toledo & Bardot (2009): Nature 460, 466-467 DNA breaks ATM kinase DNA- dependent kinase ATR kinase p14 ARF UV, stress Oncogenes p53 stabilisation Block angiogenesis
  • Summary p53 Cancer: three birds with one stone Toledo & Bardot (2009): Nature 460, 466-467 DNA breaks ATM kinase DNA- dependent kinase ATR kinase p14 ARF UV, stress Oncogenes p53 stabilisation Block angiogenesis
  • Role of p53 in induction of pluripotent stem cells
    • Krizhanovsky & Lowe (2009) Stem cells: the promises and perils of p53 Nature 460: 1085-1086
  • Role of p53 in induction of pluripotent stem cells
    • Krizhanovsky & Lowe (2009) Stem cells: the promises and perils of p53 Nature 460: 1085-1086
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