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Transcript
Laurent Le Cam (Institut de Recherche en Cancérologie de Montpellier) The P53 pathway and metabolism: implications in tissue homeostasis, aging and carcinogenesis WHY DO WE AGE AND GET CANCER? ARE THESE 2 PROCESSES INTRINSICALLY LINKED? Many stresses leads to cellular senescence Many stresses leads to cellular senescence Replicative senescence Replicative senescence Telomere shortening triggers DDR Many stresses lead to cellular senescence Oncogene induced senescence Many stresses lead to cellular senescence Stress induced senescence / premature senescence Oncogene induced senescence Definition and features of cellular senescence Pre-Senescent primary fibroblastsSenescent primary fibroblasts Changes associated with cellular senescence: Permanent cell cycle arrest Flat morphology, vacuolized cytoplasm, condensed chromatin (SAHF) SA b-Gal positive (lysosomal changes) Senescent markers (p16, p15, ARF, PML, uPAI1) Secretory phenotype (pro-inflammatory chemokines, IGFBP,…) Changes in metabolism, DNA methylation ????? MOLECULAR PATHWAYS INVOLVED IN SENESCENCE ARE THESE 2 PROCESSES INTRINSICALLY LINKED? DO THEY INVOLVE COMMON MOLECULAR CIRCUITRIES? RB p53 E2F DP The p53 tumor suppressor is a major effector of cellular stress responses Telomere attrition Metabolic stress DNA damage Oncogenic stress Hypoxia Mitotic defects Ribosomal stress Replication defects ROS p53 p53 p53 p53 p53 p53 TARGET GENES The p53 tumor suppressor is a major effector of cellular stress responses Telomere attrition Metabolic stress Oncogenic stress DNA damage Hypoxia Mitotic defects Ribosomal stress Replication defects ROS p53 p53 p53 P21, Gadd45, cyclin G1 proliferation PAI1, PML, ME1 … senescence NOXA,Bax, PUMA…. Apoptosis p53 p53 p53 is maintained inactive in unstressed cells by the Mdm2 oncoprotein Mdm2 UB p53 UB 19S 26S Proteasome UB UB p53 and Mdm2 are involved in a negative feed back loop Mdm2 UB UB UB Acute stress response p53 UB p53 19S 26S Proteasome p53 p53 p53 p53 Mdm2 The Bmi1-ARF-p53 PATHWAY: a key regulatory pathway implicated in carcinogenesis Bmi1 Bmi 1 Arf ARF MDM2/MdmX p53 p53 Mdm2 The Bmi1-ARF-p53 PATHWAY: a key regulatory pathway implicated in carcinogenesis Bmi1 Oncogene Bmi 1 Arf ARF Oncogene p53 Tumor suppressor gene p53 Tumor suppressor gene MDM2/MdmX Mdm2 ALTERATIONS OF THE p53 PATHWAY DURING TUMORIGENESIS Amplification, viral insertion Bmi1 (medulloblastomas, lymphomas) Deletion ARF Mutation Methylation Amplification MDM2 p53 Mutation Inactivation by viral oncoproteins (Li-Fraumeni Syndrome) The E2F/RB pathway THE POCKET PROTEIN FAMILY pRB, p130, p107 POCKET PROTEIN THE E2F FAMILY E2F1, E2F2, E2F3 E2F4, E2F5 E2F6, E2F7, E2F8 E2F DP TNTCC/GCG C THE DP FAMILY DP 1 DP 2 ROLE OF THE RB PATHWAY IN CELL CYCLE CONTROL INK4 (p15, p16, p18, p19) CIP/KIP (p21, p27, p57) cyclins E cdk2 cyclins D P Cdk4/6 P P P P RB RB E2F DP E2F DP cyclin E GO G1 G1 / S THE « RB » PATHWAY p16 Oncogene cyclin D cdk4/6 pRB Oncogene Oncogene Tumor suppressor gene E2F cyclin E Tumor suppressor gene GENETIC ALTERATIONS OF THE RB PATHWAY DURING TUMORIGENESIS Deletion Mutation Methylation p16 Amplification Overexpression Deletion Mutation Inactivation by viral oncoproteins cycline D cdk4/6 pRB (retinoblastomas) E2F Amplification Overexpression Mutation Binding to small inhibitors (familial melanoma predisposition) cycline E Mutation (E2F-4) Amplification (E2F-5) CROSSTALKS BETWEEN THE RB AND p53 PATHWAYS Bmi1 p16 cyclin D cdk4/6 ARF MDM2 pRB p53 E2F p21 cyclin E The INK4a/ARF locus is at the crossroads of the Rb and p53 pathways p19ARF Bmi1 Exon 1b cyclin D p16 Exon 1a Exon 3 Exon 2 INK4a/ARF locus p16 Bmi1 cdk4/6 ARF pRB E2F cyclins E, A the « pRB pathway » MDM2 p53 p21, Mdm2, PUMA…. the « p53 pathway » The Rb and p53 pathways are key regulators of senescence the « pRB pathway » cyclin D the « p53 pathway » p16 Bmi1 cdk4/6 ARF pRB E2F cyclins E, A MDM2 p53 p21, Mdm2, PUMA…. SAHF: senescence associated heterochromatin foci Senescent primary fibroblasts HP1g / transcription shut off H3K9 Tri-me+ Changes associated with cellular senescence: Permanent cell cycle arrest Flat morphology, vacuolized cytoplasm, condensed chromatin (SAHF) SA b-Gal positive (lysosomal changes) Senescent markers (p16, p15, ARF, PML, uPAI1) Secretory phenotype (pro-inflammatory chemokines, IGFBP,…) Changes in metabolism, DNA methylation ????? Yet not all senescent cells are equal !!!! Replicative senescence Oncogene induced senescence Different metabolic profiles !!!! SASP: senescence associated secretory phenotype Senescent primary fibroblasts Il6, Il8, IGFBP7, PAI1… Changes associated with cellular senescence: Permanent cell cycle arrest Flat morphology, vacuolized cytoplasm, condensed chromatin (SAHF) SA b-Gal positive (lysosomal changes) Senescent markers (p16, p15, ARF, PML, uPAI1) Secretory phenotype (pro-inflammatory chemokines, IGFBP,…) Changes in metabolism, DNA methylation ????? Senescence: a potent barrier to tumorigenesis Cell cycle arrest, inflammatory response Cellule normale Cellule sénescente Cellule inflammatoire chimiokines cytokines Tissu norma l cellules subissant des altérations oncogéniques Réponse anti-tumorale Deregulation of the p53 and Rb pathways is involved in tumorigenesis p53 p53 RB p53 p53 E2F DP Aging TUMORIGENESIS Senescence: a potent barrier to tumorigenesis Senescence is not an in vitro artefact Adenoma (benign tumor) Adenocarcinoma (malignant tumor) Senescence: a potent barrier to tumorigenesis P53 ON/OFF in vivo models p53 CONDITIONAL KNOCK-IN Lox-P p53 STOP CONDITIONAL p53 shRNA Lox-P rtTA shRNA p53 Senescence: a potent barrier to tumorigenesis P53 ON/OFF in vivo models p53 CONDITIONAL KNOCK-IN Lox-P p53 STOP CONDITIONAL p53 shRNA Lox-P rtTA shRNA p53 Senescence can participate in organismal aging p53 p53 RB p53 p53 E2F DP Tumorigenesis AGING Cellule normale Cellule sénescente Tissu jeune Cellule inflammatoire chimiokines cytokines Tissu âgé (altérations du renouvellement tissulaire) Vieillissement Senescent cells participate to organismal aging P16-suicide gene (inducible KNOCK-IN) p16 FKBP-Caspase 8 Senescent cells participate to organismal aging senescence Stem cell potential Tissue self renewal Organismal aging Senescent cells participate to organismal aging senescence Stem cell potential (Rapid regenerative tissues) Tissue self renewal Metabolic defects (Slow regenerative tissues) Tissue dysfunction Organismal aging Mitochondria play a critical role in cellular senescence Cell metabolism and energy Replicative senescence and oncogeneinduced senescence Reactive Oxygen Species (DCFDA) Decisions life and death: membrane permability leads to the release of proapoptotic mediators METABOLIC CHANGES IN SENESCENT CELLS METABOLIC CHANGES IN SENESCENT CELLS p53 Telomere attrition p53 p53 p53 p53 p53 and metabolism Glycolysis Glutamine / Glutamate metabolism Pentose phosphate pathway Glut 1,3,4 Gls2 HK2 Tigar Malate metabolism G6PD Slc7A11 ME1,2,3 PGM PI3K-AKT-mTor pathway Srebp1 p53 Biosynthesis PTEN Lipid metabolism AMPK TSC2 Gamt Polg IGFBP3 Sco2 Tfam Gpx1 Sestrins 1,2 REDOX Lpin Pgc1a Aldh4 Sod2 OXPHOS / mitochondrial biogenesis Cpt1c Acad11 b-oxidation P53 regulates metabolism p53 p53 p53 The p53 tumor suppressor regulates autophagy p53 p53 The Bmi1-ARF-p53 PATHWAY: a key regulatory pathway implicated in carcinogenesis Bmi1 Bmi 1 Arf ARF MDM2/MdmX p53 p53 Mdm2 The p53 pathway and metabolism Pentose phosphate pathway Glycolysis Glutamine / Glutamate metabolism E4F1 p53 p53 Glut 1,3,4 p53 Mdm2 Tigar Dlat, Dld, Mpc1 Malate metabolism Gls2 Slc7A11 p53 PI3K-AKT-mTor pathway E4F1 p53 ME1,2,3 Pten Ampk1 Tsc2 Igfbp3 Foxo3a InsR E4F1 Phgdh Psat E4F1 p53 Srebp1 Biosynthesis Scd1 Mdm2 Serine metabolism p53 Mdm2 p53 Lipid metabolism p53 Gamt Lpin Psph Shmt REDOX p53 Mdm2 Cpt1c E4F1 p53 Gpx1 Sestrins 1,2 Aldh4 Sod2 Sco2 Tfam Acad11 Pgc1a/b Ndufs5 OXPHOS / mitochondrial biogenesis b-oxidation WHY DO WE AGE AND GET CANCER? ARE THESE 2 PROCESSES INTRINSICALLY LINKED? p53 RB The “antagonistic pleiotropy” theory: What is good early in life might be deleterious later and promote aging p53 in aging: a puzzling question WT P53 Tg Increased p53 activity leads to premature aging phenotypes p53 (D exons 1-6) P53 mutant mice that display early ageing associated phenotypes (Tyner et al., 2002 Nature) p53 in aging: a puzzling question Extra-copies of the p53 and/or Arf loci increases lifespan WT P53/Arf Tg (super p53 + ARF, BAC transgenic strategy) p53 in aging: dosage matters !!! P53-mediated regulation of redox potential: implication in aging
