TP53 Regulates Transcription of Cell Death Genes (Homo sapiens)

From WikiPathways

Jump to: navigation, search
1, 3, 4, 8, 10...9133, 83, 87105278411151, 10, 32, 7317, 249, 10251, 593429, 60, 80, 87, 9942, 88, 936713, 16, 8616, 8635, 49, 54, 74, 924533, 87, 90983440, 558, 7833, 87, 9024, 101981, 10, 26, 32, 73...33, 83, 87117, 7124917510556, 60368, 63, 70, 7847, 5215, 794, 57, 60, 1041621, 53, 82, 85, 100...45, 81, 9710249, 8925, 4753, 82, 1005191614, 72, 756722, 3451, 59, 61, 684, 57, 60, 10444, 864229, 60, 80, 87, 99365, 23, 10256, 6040, 554646711927, 31, 41, 85, 100nucleoplasmmitochondrial matrixcytosolendosome membranemitochondrionBIRC5TP53INP1 GeneTP53I3 DimerTP53AIP1 Gene p-S15,S20-TP53Tetramer:TRIAP1Gene(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BAX Genep-S15,S20-TP53 p-S15,S20-TP53TetramerCASP10 Gene TP53AIP1 Genep-S15,S20-TP53:NLRC4GenePRELID3A p-S15,S20-TP53 p-S15,S20-TP53Tetramer:CASP10GeneIron uptake andtransportTP63 STEAP3CASP1 GeneRABGGTB TNFRSF10D Gene STEAP3 Genep-S15,S20-TP53 CRADDTP53I3 p-S15,S20-TP53Tetramer:PIDD1 GenePPP1R13B p-S15,S20-TP53Tetramer:BID Genep-S15,S20-TP53Tetramer:BCL6 GeneInterleukin-1processingp-S15,S20-TP53 CASP2(2-452) TP53I3TP63 p-S15,S20-TP53Tetramer:BCL2L14Genep-S15,S20-TP53 p-S15,S20-TP53Tetramer:TP53INP1GenePERP Genep-S15,S20-TP53 (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BBC3 Genep-S15,S20-TP53 p-S15,S20-TP53 p-S15,S20-TP53Tetramer:NDRG1 GeneFAS GeneO2.-TNFRSF10C TP53BP2 NLRC4 GeneTP53BP2 IGFBP3 Gene PERPTP63 TP73 p-S15,S20-TP53 CREBBPp-S15,S20,S46-TP53 RGGT:CHMAIFM2 Genep-T788-PIDD1 p-S15,S20-TP53 O2RABGGTA Genep-S15,S20-TP53 Regulation ofInsulin-like GrowthFactor (IGF)transport anduptake byInsulin-like GrowthFactor BindingProteins (IGFBPs)ZNF420:TP53AIP1 GeneBID GeneTP73 NADPHBAXCASP6 Gene BNIP3LApoptotic executionphaseADPp-S15,S20,S46-TP53TetramerPAPMAIP1 Gene TMEM219TNFRSF10A Gene BBC3 Gene p-S15,S20-TP53Tetramer:TNFRSF10A,TNFRSF10B,TNFRSF10C,TNFRSF10D Genesp-S15,S20-TP53 p-T788-PIDD1BCL6 GeneTNFRSF10A Gene TP53BP2 TNFRSF10D Gene TRIAP1 IGFBP3 PPP1R13B p-S1981,Ac-K3016-ATMp-S15,S20-TP53Tetramer:CASP6 GeneBIRC5 Gene p-S15,S20-TP53 RABGGTB FAS Gene AIFM2 Gene TP63 Intrinsic Pathwayfor ApoptosisBAX gene PMAIP1p-S15,S20-TP53 p-S15,S20-TP53 TNFRSF10B p-S15,S20-TP53 PRELID1 TP73 PERP Gene TP73 TRIAP1CHM CASP1 Gene BNIP3L Genep-S15,S20-TP53Tetramer:RABGGTAGeneTP73 CASP1(1-404)TNFRSF10B Gene TP63 p-S15,S20-TP53 NDRG1 Gene 1,2-NaphthoquinoneATPFasL/ CD95LsignalingBCL6 Gene p-S15,S20-TP53 (p-S15,S20-TP53,TP63):PERP GeneTNFRSF10A,TNFRSF10B,TNFRSF10C,TNFRSF10DTP73 ZNF420PIDD1 Genep-S15,S20-TP53Tetramer:APAF1 Genep-S15,S20,S46-TP53Tetramer:TP53AIP1GeneInnate Immune SystemTP73 ADPTP53BP2 CREBBP TP53INP1 Gene p-S15,S20-TP53 APAF1 geneCRADD p-S15,S20-TP53Tetramer:PMAIP1Genep-S15,S20,S46-TP53 PRELID3A IGFBP3:TMEM219BCL2L14 Gene TNFRSF10A,TNFRSF10B,TNFRSF10C,TNFRSF10D GenesRABGGTATRAIL signalingBBC3 GeneCASP10 GeneAIFM2semiquinonep-S15,S20-TP53,TP63,TP73RGGTRABGGTA (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):FAS GeneTRIAP1:PRELID1,PRELID3ATNFRSF10C Gene BNIP3L Gene CASP2(170-325)TNFRSF10A p-S15,S20-TP53 RABGGTA Gene p-S15,S20-TP53Tetramer:AIFM2 GeneNDRG1 GeneATPIGFBP3p-S15,S20-TP53 p-S15,S20-TP53Tetramer:BIRC5 GeneTP53INP1PRELID1, PRELID3Ap-S15,S20-TP53 CASP2(348-452)PPP1R13B BCL6PAp-S15,S20-TP53 TP53I3 Gene(p-S15,S20-TP53,TP63,TP73):CASP1 GeneBIRC5 GeneRegulation of TP53ActivityBCL2L14 Genep-S15,S20-TP53 TP53BP2 PMAIP1 GeneTMEM219 NADP+TRIAP1 Genep-T788-PIDD1STEAP3 Gene CRADD TNFRSF10D PIDDosome:CASP2(2-452)p-S15,S20-TP53 BBC3CHMNLRC4 Gene CASP2(2-452)p-S15,S20-TP53Tetramer:STEAP3GeneCASP6 GeneRABGGTB(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):TP53I3 Genep-S15,S20-TP53,TP63TP53I3 Gene TNFRSF10C Gene ZNF420 CASP6 (1-293)FASp-S15,S20-TP53Tetramer:CREBBP:BNIP3L GeneTP63 PRELID1 (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)CASP10(1-521)TNFRSF10B Gene TP53AIP1p-S15,S20-TP53 BNIP3L p-T788-PIDD1 p-S15,S20-TP53 PIDD1STEAP3:BNIP3LH+PPP1R13B STEAP3 PIDD1 Gene TRIAP1 Gene APAF1 gene TP53AIP1 Gene IGFBP3 GeneTP63 p-S15,S20-TP53 p-S15,S20-TP53Tetramer:IGFBP3GenePIDDosomeRABGGTA p-S15,S20-TP53 APAF1BID(1-195)NDRG1p-S68-ZNF420BID Gene BAX geneTP63 NLRC4BCL2L14PPP1R13B TP63 517, 243655758, 782, 38, 95276, 18, 28, 764, 10451, 592467779146428349861153, 82, 100102651054756, 6084349029, 9943, 58, 6449159820, 30, 37, 39, 50...851213, 16, 861, 10, 32, 73714519


Description

The tumor suppressor TP53 (p53) exerts its tumor suppressive role in part by regulating transcription of a number of genes involved in cell death, mainly apoptotic cell death. The majority of apoptotic genes that are transcriptional targets of TP53 promote apoptosis, but there are also several TP53 target genes that inhibit apoptosis, providing cells with an opportunity to attempt to repair the damage and/or recover from stress.
Pro-apoptotic transcriptional targets of TP53 involve TRAIL death receptors TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2), as well as the FASL/CD95L death receptor FAS (CD95). TRAIL receptors and FAS induce pro-apoptotic signaling in response to external stimuli via extrinsic apoptosis pathway (Wu et al. 1997, Takimoto et al. 2000, Guan et al. 2001, Liu et al. 2004, Ruiz de Almodovar et al. 2004, Liu et al. 2005, Schilling et al. 2009, Wilson et al. 2013). IGFBP3 is a transcriptional target of TP53 that may serve as a ligand for a novel death receptor TMEM219 (Buckbinder et al. 1995, Ingermann et al. 2010).

TP53 regulates expression of a number of genes involved in the intrinsic apoptosis pathway, triggered by the cellular stress. Some of TP53 targets, such as BAX, BID, PMAIP1 (NOXA), BBC3 (PUMA) and probably BNIP3L, AIFM2, STEAP3, TRIAP1 and TP53AIP1, regulate the permeability of the mitochondrial membrane and/or cytochrome C release (Miyashita and Reed 1995, Oda et al. 2000, Samuels-Lev et al. 2001, Nakano and Vousden 2001, Sax et al. 2002, Passer et al. 2003, Bergamaschi et al. 2004, Li et al. 2004, Fei et al. 2004, Wu et al. 2004, Park and Nakamura 2005, Patel et al. 2008, Wang et al. 2012, Wilson et al. 2013). Other pro-apoptotic genes, either involved in the intrinsic apoptosis pathway, extrinsic apoptosis pathway or pyroptosis (inflammation-related cell death), which are transcriptionally regulated by TP53 are cytosolic caspase activators, such as APAF1, PIDD1, and NLRC4, and caspases themselves, such as CASP1, CASP6 and CASP10 (Lin et al. 2000, Robles et al. 2001, Gupta et al. 2001, MacLachlan and El-Deiry 2002, Rikhof et al. 2003, Sadasivam et al. 2005, Brough and Rothwell 2007).<p>It is uncertain how exactly some of the pro-apoptotic TP53 targets, such as TP53I3 (PIG3), RABGGTA, BCL2L14, BCL6, NDRG1 and PERP contribute to apoptosis (Attardi et al. 2000, Guo et al. 2001, Samuels-Lev et al. 2001, Contente et al. 2002, Ihrie et al. 2003, Bergamaschi et al. 2004, Stein et al. 2004, Phan and Dalla-Favera 2004, Jen and Cheung 2005, Margalit et al. 2006, Zhang et al. 2007, Saito et al. 2009, Davies et al. 2009, Giam et al. 2012).<p>TP53 is stabilized in response to cellular stress by phosphorylation on at least serine residues S15 and S20. Since TP53 stabilization precedes the activation of cell death genes, the TP53 tetramer phosphorylated at S15 and S20 is shown as a regulator of pro-apoptotic/pro-cell death genes. Some pro-apoptotic TP53 target genes, such as TP53AIP1, require additional phosphorylation of TP53 at serine residue S46 (Oda et al. 2000, Taira et al. 2007). Phosphorylation of TP53 at S46 is regulated by another TP53 pro-apoptotic target, TP53INP1 (Okamura et al. 2001, Tomasini et al. 2003). Additional post-translational modifications of TP53 may be involved in transcriptional regulation of genes presented in this pathway and this information will be included as evidence becomes available.<p>Activation of some pro-apoptotic TP53 targets, such as BAX, FAS, BBC3 (PUMA) and TP53I3 (PIG3) requires the presence of the complex of TP53 and an ASPP protein, either PPP1R13B (ASPP1) or TP53BP2 (ASPP2) (Samuels-Lev et al. 2001, Bergamaschi et al. 2004, Patel et al. 2008, Wilson et al. 2013), indicating how the interaction with specific co-factors modulates the cellular response/outcome.<p>TP53 family members TP63 and or TP73 can also activate some of the pro-apoptotic TP53 targets, such as FAS, BAX, BBC3 (PUMA), TP53I3 (PIG3), CASP1 and PERP (Bergamaschi et al. 2004, Jain et al. 2005, Ihrie et al. 2005, Patel et al. 2008, Schilling et al. 2009, Celardo et al. 2013).<p>
For a review of the role of TP53 in apoptosis and pro-apoptotic transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015. View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 5633008
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Liu X, Yue P, Khuri FR, Sun SY.; ''Decoy receptor 2 (DcR2) is a p53 target gene and regulates chemosensitivity.''; PubMed Europe PMC
  2. Kurz T, Terman A, Gustafsson B, Brunk UT.; ''Lysosomes in iron metabolism, ageing and apoptosis.''; PubMed Europe PMC
  3. Bieging KT, Mello SS, Attardi LD.; ''Unravelling mechanisms of p53-mediated tumour suppression.''; PubMed Europe PMC
  4. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N.; ''Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.''; PubMed Europe PMC
  5. Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, Nishimori H, Tamai K, Tokino T, Nakamura Y, Taya Y.; ''p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53.''; PubMed Europe PMC
  6. Mantovani F, Zannini A, Rustighi A, Del Sal G.; ''Interaction of p53 with prolyl isomerases: Healthy and unhealthy relationships.''; PubMed Europe PMC
  7. Andrysik Z, Kim J, Tan AC, Espinosa JM.; ''A genetic screen identifies TCF3/E2A and TRIAP1 as pathway-specific regulators of the cellular response to p53 activation.''; PubMed Europe PMC
  8. Stein S, Thomas EK, Herzog B, Westfall MD, Rocheleau JV, Jackson RS, Wang M, Liang P.; ''NDRG1 is necessary for p53-dependent apoptosis.''; PubMed Europe PMC
  9. Tian C, Xing G, Xie P, Lu K, Nie J, Wang J, Li L, Gao M, Zhang L, He F.; ''KRAB-type zinc-finger protein Apak specifically regulates p53-dependent apoptosis.''; PubMed Europe PMC
  10. Takimoto R, El-Deiry WS.; ''Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site.''; PubMed Europe PMC
  11. Jen KY, Cheung VG.; ''Identification of novel p53 target genes in ionizing radiation response.''; PubMed Europe PMC
  12. Hengartner MO.; ''The biochemistry of apoptosis.''; PubMed Europe PMC
  13. Nematollahi LA, Garza-Garcia A, Bechara C, Esposito D, Morgner N, Robinson CV, Driscoll PC.; ''Flexible stoichiometry and asymmetry of the PIDDosome core complex by heteronuclear NMR spectroscopy and mass spectrometry.''; PubMed Europe PMC
  14. Saito M, Novak U, Piovan E, Basso K, Sumazin P, Schneider C, Crespo M, Shen Q, Bhagat G, Califano A, Chadburn A, Pasqualucci L, Dalla-Favera R.; ''BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma.''; PubMed Europe PMC
  15. Robles AI, Bemmels NA, Foraker AB, Harris CC.; ''APAF-1 is a transcriptional target of p53 in DNA damage-induced apoptosis.''; PubMed Europe PMC
  16. Ando K, Kernan JL, Liu PH, Sanda T, Logette E, Tschopp J, Look AT, Wang J, Bouchier-Hayes L, Sidi S.; ''PIDD death-domain phosphorylation by ATM controls prodeath versus prosurvival PIDDosome signaling.''; PubMed Europe PMC
  17. Hamacher-Brady A, Choe SC, Krijnse-Locker J, Brady NR.; ''Intramitochondrial recruitment of endolysosomes mediates Smac degradation and constitutes a novel intrinsic apoptosis antagonizing function of XIAP E3 ligase.''; PubMed Europe PMC
  18. Meek DW, Anderson CW.; ''Posttranslational modification of p53: cooperative integrators of function.''; PubMed Europe PMC
  19. Fei P, Wang W, Kim SH, Wang S, Burns TF, Sax JK, Buzzai M, Dicker DT, McKenna WG, Bernhard EJ, El-Deiry WS.; ''Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth.''; PubMed Europe PMC
  20. Schneider MR, Zhou R, Hoeflich A, Krebs O, Schmidt J, Mohan S, Wolf E, Lahm H.; ''Insulin-like growth factor-binding protein-5 inhibits growth and induces differentiation of mouse osteosarcoma cells.''; PubMed Europe PMC
  21. Miura M, Zhu H, Rotello R, Hartwieg EA, Yuan J.; ''Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3.''; PubMed Europe PMC
  22. Oppermann U.; ''Carbonyl reductases: the complex relationships of mammalian carbonyl- and quinone-reducing enzymes and their role in physiology.''; PubMed Europe PMC
  23. Taira N, Nihira K, Yamaguchi T, Miki Y, Yoshida K.; ''DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage.''; PubMed Europe PMC
  24. Passer BJ, Nancy-Portebois V, Amzallag N, Prieur S, Cans C, Roborel de Climens A, Fiucci G, Bouvard V, Tuynder M, Susini L, Morchoisne S, Crible V, Lespagnol A, Dausset J, Oren M, Amson R, Telerman A.; ''The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and interacts with Nix and the Myt1 kinase.''; PubMed Europe PMC
  25. Grimberg A, Coleman CM, Burns TF, Himelstein BP, Koch CJ, Cohen P, El-Deiry WS.; ''p53-Dependent and p53-independent induction of insulin-like growth factor binding protein-3 by deoxyribonucleic acid damage and hypoxia.''; PubMed Europe PMC
  26. Guan B, Yue P, Clayman GL, Sun SY.; ''Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene.''; PubMed Europe PMC
  27. Sadasivam S, Gupta S, Radha V, Batta K, Kundu TK, Swarup G.; ''Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis.''; PubMed Europe PMC
  28. Kruse JP, Gu W.; ''Modes of p53 regulation.''; PubMed Europe PMC
  29. Han J, Flemington C, Houghton AB, Gu Z, Zambetti GP, Lutz RJ, Zhu L, Chittenden T.; ''Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals.''; PubMed Europe PMC
  30. Holly J, Perks C.; ''The role of insulin-like growth factor binding proteins.''; PubMed Europe PMC
  31. Schroder K, Tschopp J.; ''The inflammasomes.''; PubMed Europe PMC
  32. Liu X, Yue P, Khuri FR, Sun SY.; ''p53 upregulates death receptor 4 expression through an intronic p53 binding site.''; PubMed Europe PMC
  33. Samuels-Lev Y, O'Connor DJ, Bergamaschi D, Trigiante G, Hsieh JK, Zhong S, Campargue I, Naumovski L, Crook T, Lu X.; ''ASPP proteins specifically stimulate the apoptotic function of p53.''; PubMed Europe PMC
  34. Porté S, Valencia E, Yakovtseva EA, Borràs E, Shafqat N, Debreczeny JE, Pike AC, Oppermann U, Farrés J, Fita I, Parés X.; ''Three-dimensional structure and enzymatic function of proapoptotic human p53-inducible quinone oxidoreductase PIG3.''; PubMed Europe PMC
  35. Lackner MR, Kindt RM, Carroll PM, Brown K, Cancilla MR, Chen C, de Silva H, Franke Y, Guan B, Heuer T, Hung T, Keegan K, Lee JM, Manne V, O'Brien C, Parry D, Perez-Villar JJ, Reddy RK, Xiao H, Zhan H, Cockett M, Plowman G, Fitzgerald K, Costa M, Ross-Macdonald P.; ''Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors.''; PubMed Europe PMC
  36. Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M, Nakamura Y.; ''p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis.''; PubMed Europe PMC
  37. Zhou R, Diehl D, Hoeflich A, Lahm H, Wolf E.; ''IGF-binding protein-4: biochemical characteristics and functional consequences.''; PubMed Europe PMC
  38. Hower V, Mendes P, Torti FM, Laubenbacher R, Akman S, Shulaev V, Torti SV.; ''A general map of iron metabolism and tissue-specific subnetworks.''; PubMed Europe PMC
  39. Hoeflich A, Reisinger R, Lahm H, Kiess W, Blum WF, Kolb HJ, Weber MM, Wolf E.; ''Insulin-like growth factor-binding protein 2 in tumorigenesis: protector or promoter?''; PubMed Europe PMC
  40. Miliara X, Garnett JA, Tatsuta T, Abid Ali F, Baldie H, Pérez-Dorado I, Simpson P, Yague E, Langer T, Matthews S.; ''Structural insight into the TRIAP1/PRELI-like domain family of mitochondrial phospholipid transfer complexes.''; PubMed Europe PMC
  41. Poyet JL, Srinivasula SM, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri ES.; ''Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1.''; PubMed Europe PMC
  42. Miled C, Pontoglio M, Garbay S, Yaniv M, Weitzman JB.; ''A genomic map of p53 binding sites identifies novel p53 targets involved in an apoptotic network.''; PubMed Europe PMC
  43. Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P.; ''Toxic proteins released from mitochondria in cell death.''; PubMed Europe PMC
  44. Berube C, Boucher LM, Ma W, Wakeham A, Salmena L, Hakem R, Yeh WC, Mak TW, Benchimol S.; ''Apoptosis caused by p53-induced protein with death domain (PIDD) depends on the death adapter protein RAIDD.''; PubMed Europe PMC
  45. Rikhof B, Corn PG, El-Deiry WS.; ''Caspase 10 levels are increased following DNA damage in a p53-dependent manner.''; PubMed Europe PMC
  46. Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS.; ''BID regulation by p53 contributes to chemosensitivity.''; PubMed Europe PMC
  47. Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR, Kley N.; ''Induction of the growth inhibitor IGF-binding protein 3 by p53.''; PubMed Europe PMC
  48. Riley T, Sontag E, Chen P, Levine A.; ''Transcriptional control of human p53-regulated genes.''; PubMed Europe PMC
  49. Baron RA, Seabra MC.; ''Rab geranylgeranylation occurs preferentially via the pre-formed REP-RGGT complex and is regulated by geranylgeranyl pyrophosphate.''; PubMed Europe PMC
  50. Mohan S, Baylink DJ.; ''IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms.''; PubMed Europe PMC
  51. Ihrie RA, Marques MR, Nguyen BT, Horner JS, Papazoglu C, Bronson RT, Mills AA, Attardi LD.; ''Perp is a p63-regulated gene essential for epithelial integrity.''; PubMed Europe PMC
  52. Marzec KA, Lin MZ, Martin JL, Baxter RC.; ''Involvement of p53 in insulin-like growth factor binding protein-3 regulation in the breast cancer cell response to DNA damage.''; PubMed Europe PMC
  53. Jain N, Gupta S, Sudhakar Ch, Radha V, Swarup G.; ''Role of p73 in regulating human caspase-1 gene transcription induced by interferon-{gamma} and cisplatin.''; PubMed Europe PMC
  54. Farnsworth CC, Seabra MC, Ericsson LH, Gelb MH, Glomset JA.; ''Rab geranylgeranyl transferase catalyzes the geranylgeranylation of adjacent cysteines in the small GTPases Rab1A, Rab3A, and Rab5A.''; PubMed Europe PMC
  55. Potting C, Tatsuta T, König T, Haag M, Wai T, Aaltonen MJ, Langer T.; ''TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid.''; PubMed Europe PMC
  56. Schilling T, Schleithoff ES, Kairat A, Melino G, Stremmel W, Oren M, Krammer PH, Müller M.; ''Active transcription of the human FAS/CD95/TNFRSF6 gene involves the p53 family.''; PubMed Europe PMC
  57. Wang L, Xing H, Tian Z, Peng L, Li Y, Tang K, Rao Q, Wang M, Wang J.; ''iASPPsv antagonizes apoptosis induced by chemotherapeutic agents in MCF-7 cells and mouse thymocytes.''; PubMed Europe PMC
  58. Wang X.; ''The expanding role of mitochondria in apoptosis.''; PubMed Europe PMC
  59. Attardi LD, Reczek EE, Cosmas C, Demicco EG, McCurrach ME, Lowe SW, Jacks T.; ''PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family.''; PubMed Europe PMC
  60. Wilson AM, Morquette B, Abdouh M, Unsain N, Barker PA, Feinstein E, Bernier G, Di Polo A.; ''ASPP1/2 regulate p53-dependent death of retinal ganglion cells through PUMA and Fas/CD95 activation in vivo.''; PubMed Europe PMC
  61. Davies L, Gray D, Spiller D, White MR, Damato B, Grierson I, Paraoan L.; ''P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma.''; PubMed Europe PMC
  62. Murray-Zmijewski F, Slee EA, Lu X.; ''A complex barcode underlies the heterogeneous response of p53 to stress.''; PubMed Europe PMC
  63. Sun J, Zhang D, Bae DH, Sahni S, Jansson P, Zheng Y, Zhao Q, Yue F, Zheng M, Kovacevic Z, Richardson DR.; ''Metastasis suppressor, NDRG1, mediates its activity through signaling pathways and molecular motors.''; PubMed Europe PMC
  64. Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMed Europe PMC
  65. Wang S, El-Deiry WS.; ''TRAIL and apoptosis induction by TNF-family death receptors.''; PubMed Europe PMC
  66. Tomasini R, Samir AA, Carrier A, Isnardon D, Cecchinelli B, Soddu S, Malissen B, Dagorn JC, Iovanna JL, Dusetti NJ.; ''TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity.''; PubMed Europe PMC
  67. Wu M, Xu LG, Su T, Tian Y, Zhai Z, Shu HB.; ''AMID is a p53-inducible gene downregulated in tumors.''; PubMed Europe PMC
  68. Ihrie RA, Reczek E, Horner JS, Khachatrian L, Sage J, Jacks T, Attardi LD.; ''Perp is a mediator of p53-dependent apoptosis in diverse cell types.''; PubMed Europe PMC
  69. Kruiswijk F, Labuschagne CF, Vousden KH.; ''p53 in survival, death and metabolic health: a lifeguard with a licence to kill.''; PubMed Europe PMC
  70. Song Y, Cao L.; ''N-myc downstream-regulated gene 1: Diverse and complicated functions in human hepatocellular carcinoma (Review).''; PubMed Europe PMC
  71. Park WR, Nakamura Y.; ''p53CSV, a novel p53-inducible gene involved in the p53-dependent cell-survival pathway.''; PubMed Europe PMC
  72. Phan RT, Dalla-Favera R.; ''The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells.''; PubMed Europe PMC
  73. Ruiz de Almodóvar C, Ruiz-Ruiz C, Rodríguez A, Ortiz-Ferrón G, Redondo JM, López-Rivas A.; ''Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) decoy receptor TRAIL-R3 is up-regulated by p53 in breast tumor cells through a mechanism involving an intronic p53-binding site.''; PubMed Europe PMC
  74. Thomä NH, Iakovenko A, Goody RS, Alexandrov K.; ''Phosphoisoprenoids modulate association of Rab geranylgeranyltransferase with REP-1.''; PubMed Europe PMC
  75. Margalit O, Amram H, Amariglio N, Simon AJ, Shaklai S, Granot G, Minsky N, Shimoni A, Harmelin A, Givol D, Shohat M, Oren M, Rechavi G.; ''BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma.''; PubMed Europe PMC
  76. Santiago A, Li D, Zhao LY, Godsey A, Liao D.; ''p53 SUMOylation promotes its nuclear export by facilitating its release from the nuclear export receptor CRM1.''; PubMed Europe PMC
  77. Fischer U, Jänicke RU, Schulze-Osthoff K.; ''Many cuts to ruin: a comprehensive update of caspase substrates.''; PubMed Europe PMC
  78. Zhang AH, Rao JN, Zou T, Liu L, Marasa BS, Xiao L, Chen J, Turner DJ, Wang JY.; ''p53-dependent NDRG1 expression induces inhibition of intestinal epithelial cell proliferation but not apoptosis after polyamine depletion.''; PubMed Europe PMC
  79. Hu Y, Benedict MA, Ding L, Núñez G.; ''Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis.''; PubMed Europe PMC
  80. Patel S, George R, Autore F, Fraternali F, Ladbury JE, Nikolova PV.; ''Molecular interactions of ASPP1 and ASPP2 with the p53 protein family and the apoptotic promoters PUMA and Bax.''; PubMed Europe PMC
  81. Wang J, Chun HJ, Wong W, Spencer DM, Lenardo MJ.; ''Caspase-10 is an initiator caspase in death receptor signaling.''; PubMed Europe PMC
  82. Celardo I, Grespi F, Antonov A, Bernassola F, Garabadgiu AV, Melino G, Amelio I.; ''Caspase-1 is a novel target of p63 in tumor suppression.''; PubMed Europe PMC
  83. Miyashita T, Reed JC.; ''Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.''; PubMed Europe PMC
  84. Ingermann AR, Yang YF, Han J, Mikami A, Garza AE, Mohanraj L, Fan L, Idowu M, Ware JL, Kim HS, Lee DY, Oh Y.; ''Identification of a novel cell death receptor mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer.''; PubMed Europe PMC
  85. Brough D, Rothwell NJ.; ''Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death.''; PubMed Europe PMC
  86. Tinel A, Tschopp J.; ''The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress.''; PubMed Europe PMC
  87. Bergamaschi D, Samuels Y, Jin B, Duraisingham S, Crook T, Lu X.; ''ASPP1 and ASPP2: common activators of p53 family members.''; PubMed Europe PMC
  88. Guo B, Godzik A, Reed JC.; ''Bcl-G, a novel pro-apoptotic member of the Bcl-2 family.''; PubMed Europe PMC
  89. Seabra MC, Goldstein JL, Südhof TC, Brown MS.; ''Rab geranylgeranyl transferase. A multisubunit enzyme that prenylates GTP-binding proteins terminating in Cys-X-Cys or Cys-Cys.''; PubMed Europe PMC
  90. Contente A, Dittmer A, Koch MC, Roth J, Dobbelstein M.; ''A polymorphic microsatellite that mediates induction of PIG3 by p53.''; PubMed Europe PMC
  91. MacLachlan TK, El-Deiry WS.; ''Apoptotic threshold is lowered by p53 transactivation of caspase-6.''; PubMed Europe PMC
  92. Li Y, Zhao Y, Hu J, Xiao J, Qu L, Wang Z, Ma D, Chen Y.; ''A novel ER-localized transmembrane protein, EMC6, interacts with RAB5A and regulates cell autophagy.''; PubMed Europe PMC
  93. Giam M, Okamoto T, Mintern JD, Strasser A, Bouillet P.; ''Bcl-2 family member Bcl-G is not a proapoptotic protein.''; PubMed Europe PMC
  94. Firth SM, Baxter RC.; ''Cellular actions of the insulin-like growth factor binding proteins.''; PubMed Europe PMC
  95. Richardson DR, Lane DJ, Becker EM, Huang ML, Whitnall M, Suryo Rahmanto Y, Sheftel AD, Ponka P.; ''Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol.''; PubMed Europe PMC
  96. Wu GS, Burns TF, McDonald ER, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G, el-Deiry WS.; ''KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene.''; PubMed Europe PMC
  97. Sprick MR, Rieser E, Stahl H, Grosse-Wilde A, Weigand MA, Walczak H.; ''Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8.''; PubMed Europe PMC
  98. Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M.; ''Transcriptional repression of the anti-apoptotic survivin gene by wild type p53.''; PubMed Europe PMC
  99. Nakano K, Vousden KH.; ''PUMA, a novel proapoptotic gene, is induced by p53.''; PubMed Europe PMC
  100. Gupta S, Radha V, Furukawa Y, Swarup G.; ''Direct transcriptional activation of human caspase-1 by tumor suppressor p53.''; PubMed Europe PMC
  101. Lespagnol A, Duflaut D, Beekman C, Blanc L, Fiucci G, Marine JC, Vidal M, Amson R, Telerman A.; ''Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice.''; PubMed Europe PMC
  102. Yuan L, Tian C, Wang H, Song S, Li D, Xing G, Yin Y, He F, Zhang L.; ''Apak competes with p53 for direct binding to intron 1 of p53AIP1 to regulate apoptosis.''; PubMed Europe PMC
  103. Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Van Ness K, Greenstreet TA, March CJ, Kronheim SR, Druck T, Cannizzaro LA.; ''Molecular cloning of the interleukin-1 beta converting enzyme.''; PubMed Europe PMC
  104. Li CQ, Robles AI, Hanigan CL, Hofseth LJ, Trudel LJ, Harris CC, Wogan GN.; ''Apoptotic signaling pathways induced by nitric oxide in human lymphoblastoid cells expressing wild-type or mutant p53.''; PubMed Europe PMC
  105. Lin Y, Ma W, Benchimol S.; ''Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis.''; PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
101592view11:46, 1 November 2018ReactomeTeamreactome version 66
101128view21:31, 31 October 2018ReactomeTeamreactome version 65
100656view20:05, 31 October 2018ReactomeTeamreactome version 64
100206view16:50, 31 October 2018ReactomeTeamreactome version 63
99757view15:16, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99319view12:47, 31 October 2018ReactomeTeamreactome version 62
93790view13:36, 16 August 2017ReactomeTeamreactome version 61
93324view11:20, 9 August 2017ReactomeTeamreactome version 61
88393view15:16, 4 August 2016FehrhartOntology Term : 'cell death pathway' added !
88392view15:15, 4 August 2016FehrhartOntology Term : 'regulatory pathway' added !
86411view09:17, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
(p-S15,S20-TP53,TP63):PERP GeneComplexR-HSA-6800835 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BAX GeneComplexR-HSA-3700978 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BBC3 GeneComplexR-HSA-4331345 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):FAS GeneComplexR-HSA-6799810 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):TP53I3 GeneComplexR-HSA-6799461 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)ComplexR-HSA-6799788 (Reactome)
(p-S15,S20-TP53,TP63,TP73):CASP1 GeneComplexR-HSA-6798078 (Reactome)
1,2-NaphthoquinoneMetaboliteCHEBI:34055 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
AIFM2 Gene ProteinENSG00000042286 (Ensembl)
AIFM2 GeneGeneProductENSG00000042286 (Ensembl)
AIFM2ProteinQ9BRQ8 (Uniprot-TrEMBL)
APAF1 gene ProteinENSG00000120868 (Ensembl)
APAF1 geneGeneProductENSG00000120868 (Ensembl)
APAF1ProteinO14727 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Apoptotic execution phasePathwayR-HSA-75153 (Reactome) In the execution phase of apoptosis, effector caspases cleave vital cellular proteins leading to the morphological changes that characterize apoptosis. These changes include destruction of the nucleus and other organelles, DNA fragmentation, chromatin condensation, cell shrinkage and cell detachment and membrane blebbing (reviewed in Fischer et al., 2003).
BAX gene ProteinENSG00000087088 (Ensembl)
BAX geneGeneProductENSG00000087088 (Ensembl)
BAXProteinQ07812 (Uniprot-TrEMBL)
BBC3 Gene ProteinENSG00000105327 (Ensembl)
BBC3 GeneGeneProductENSG00000105327 (Ensembl)
BBC3ProteinQ9BXH1 (Uniprot-TrEMBL)
BCL2L14 Gene ProteinENSG00000121380 (Ensembl)
BCL2L14 GeneGeneProductENSG00000121380 (Ensembl)
BCL2L14ProteinQ9BZR8 (Uniprot-TrEMBL)
BCL6 Gene ProteinENSG00000113916 (Ensembl)
BCL6 GeneGeneProductENSG00000113916 (Ensembl)
BCL6ProteinP41182 (Uniprot-TrEMBL)
BID Gene ProteinENSG00000015475 (Ensembl)
BID GeneGeneProductENSG00000015475 (Ensembl)
BID(1-195)ProteinP55957 (Uniprot-TrEMBL)
BIRC5 Gene ProteinENSG00000089685 (Ensembl)
BIRC5 GeneGeneProductENSG00000089685 (Ensembl)
BIRC5ProteinO15392 (Uniprot-TrEMBL)
BNIP3L Gene ProteinENSG00000104765 (Ensembl)
BNIP3L GeneGeneProductENSG00000104765 (Ensembl)
BNIP3L ProteinO60238 (Uniprot-TrEMBL)
BNIP3LProteinO60238 (Uniprot-TrEMBL)
CASP1 Gene ProteinENSG00000137752 (Ensembl)
CASP1 GeneGeneProductENSG00000137752 (Ensembl)
CASP1(1-404)ProteinP29466 (Uniprot-TrEMBL)
CASP10 Gene ProteinENSG00000003400 (Ensembl)
CASP10 GeneGeneProductENSG00000003400 (Ensembl)
CASP10(1-521)ProteinQ92851 (Uniprot-TrEMBL)
CASP2(170-325)ProteinP42575 (Uniprot-TrEMBL)
CASP2(2-452) ProteinP42575 (Uniprot-TrEMBL)
CASP2(2-452)ProteinP42575 (Uniprot-TrEMBL)
CASP2(348-452)ProteinP42575 (Uniprot-TrEMBL)
CASP6 (1-293)ProteinP55212 (Uniprot-TrEMBL)
CASP6 Gene ProteinENSG00000138794 (Ensembl)
CASP6 GeneGeneProductENSG00000138794 (Ensembl)
CHM ProteinP24386 (Uniprot-TrEMBL)
CHMProteinP24386 (Uniprot-TrEMBL)
CRADD ProteinP78560 (Uniprot-TrEMBL)
CRADDProteinP78560 (Uniprot-TrEMBL)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CREBBPProteinQ92793 (Uniprot-TrEMBL)
FAS Gene ProteinENSG00000026103 (Ensembl)
FAS GeneGeneProductENSG00000026103 (Ensembl)
FASProteinP25445 (Uniprot-TrEMBL)
FasL/ CD95L signalingPathwayR-HSA-75157 (Reactome) The Fas family of cell surface receptors initiate the apototic pathway through interaction with the external ligand, FasL. The cytoplasmic domain of Fas interacts with a number of molecules in the transduction of the external signal to the cytoplasmic side of the cell membrane. The most notable cytoplasmic domain is the Death Domain (DD) that is involved in recruiting the FAS-associating death domain-containing protein (FADD). This interaction drives downstream events.
H+MetaboliteCHEBI:15378 (ChEBI)
IGFBP3 Gene ProteinENSG00000146674 (Ensembl)
IGFBP3 GeneGeneProductENSG00000146674 (Ensembl)
IGFBP3 ProteinP17936 (Uniprot-TrEMBL)
IGFBP3:TMEM219ComplexR-HSA-6800024 (Reactome)
IGFBP3ProteinP17936 (Uniprot-TrEMBL)
Innate Immune SystemPathwayR-HSA-168249 (Reactome) Innate immunity encompases the nonspecific part of immunity tha are part of an individual's natural biologic makeup
Interleukin-1 processingPathwayR-HSA-448706 (Reactome) The IL-1 family of cytokines that interact with the Type 1 IL-1R include IL-1α (IL1A), IL-1β (IL1B) and the IL-1 receptor antagonist protein (IL1RAP). IL1RAP is synthesized with a signal peptide and secreted as a mature protein via the classical secretory pathway. IL1A and IL1B are synthesised as cytoplasmic precursors (pro-IL1A and pro-IL1B) in activated cells. They have no signal sequence, precluding secretion via the classical ER-Golgi route (Rubartelli et al. 1990). Processing of pro-IL1B to the active form requires caspase-1 (Thornberry et al. 1992), which is itself activated by a molecular scaffold termed the inflammasome (Martinon et al. 2002). Processing and release of IL1B are thought to be closely linked, because mature IL1B is only seen inside inflammatory cells just prior to release (Brough et al. 2003). It has been reported that in monocytes a fraction of cellular IL1B is released by the regulated secretion of late endosomes and early lysosomes, and that this may represent a cellular compartment where caspase-1 processing of pro-IL1B takes place (Andrei et al. 1999). Shedding of microvesicles from the plasma membrane has also been proposed as a mechanism of secretion (MacKenzie et al. 2001). These proposals superceded previous models in which non-specific release due to cell lysis and passage through a plasma membrane pore were considered. However, there is evidence in the literature that supports all of these mechanisms and there is still controversy over how IL1B exits from cells (Brough & Rothwell 2007). A calpain-like potease has been reported to be important for the processing of pro-IL1A, but much less is known about how IL1A is released from cells and what specific roles it plays in biology.
Intrinsic Pathway for ApoptosisPathwayR-HSA-109606 (Reactome) The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:

1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption.

2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.

Iron uptake and transportPathwayR-HSA-917937 (Reactome) The transport of iron between cells is mediated by transferrin. However, iron can also enter and leave cells not only by itself, but also in the form of heme and siderophores. When entering the cell via the main path (by transferrin endocytosis), its goal is not the (still elusive) chelated iron pool in the cytosol nor the lysosomes but the mitochondria, where heme is synthesized and iron-sulfur clusters are assembled (Kurz et al,2008, Hower et al 2009, Richardson et al 2010).
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NDRG1 Gene ProteinENSG00000104419 (Ensembl)
NDRG1 GeneGeneProductENSG00000104419 (Ensembl)
NDRG1ProteinQ92597 (Uniprot-TrEMBL)
NLRC4 Gene ProteinENSG00000091106 (Ensembl)
NLRC4 GeneGeneProductENSG00000091106 (Ensembl)
NLRC4ProteinQ9NPP4 (Uniprot-TrEMBL)
O2.-MetaboliteCHEBI:18421 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PAMetaboliteCHEBI:16337 (ChEBI)
PERP Gene ProteinENSG00000112378 (Ensembl)
PERP GeneGeneProductENSG00000112378 (Ensembl)
PERPProteinQ96FX8 (Uniprot-TrEMBL)
PIDD1 Gene ProteinENSG00000177595 (Ensembl)
PIDD1 GeneGeneProductENSG00000177595 (Ensembl)
PIDD1ProteinQ9HB75 (Uniprot-TrEMBL)
PIDDosome:CASP2(2-452)ComplexR-HSA-6800803 (Reactome)
PIDDosomeComplexR-HSA-6800782 (Reactome)
PMAIP1 Gene ProteinENSG00000141682 (Ensembl)
PMAIP1 GeneGeneProductENSG00000141682 (Ensembl)
PMAIP1ProteinQ13794 (Uniprot-TrEMBL)
PPP1R13B ProteinQ96KQ4 (Uniprot-TrEMBL)
PRELID1 ProteinQ9Y255 (Uniprot-TrEMBL)
PRELID1, PRELID3AComplexR-HSA-8870822 (Reactome)
PRELID3A ProteinQ96N28 (Uniprot-TrEMBL)
RABGGTA Gene ProteinENSG00000100949 (Ensembl)
RABGGTA GeneGeneProductENSG00000100949 (Ensembl)
RABGGTA ProteinQ92696 (Uniprot-TrEMBL)
RABGGTAProteinQ92696 (Uniprot-TrEMBL)
RABGGTB ProteinP53611 (Uniprot-TrEMBL)
RABGGTBProteinP53611 (Uniprot-TrEMBL)
RGGT:CHMComplexR-HSA-6801111 (Reactome)
RGGTComplexR-HSA-6801105 (Reactome)
Regulation of

Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding

Proteins (IGFBPs)
PathwayR-HSA-381426 (Reactome) The family of Insulin like Growth Factor Binding Proteins (IGFBPs) share 50% amino acid identity with conserved N terminal and C terminal regions responsible for binding Insulin like Growth Factors I and II (IGF I and IGF II). Most circulating IGFs are in complexes with IGFBPs, which are believed to increase the residence of IGFs in the body, modulate availability of IGFs to target receptors for IGFs, reduce insulin like effects of IGFs, and act as signaling molecules independently of IGFs.

About 75% of circulating IGFs are in 1500 220 KDa complexes with IGFBP3 and ALS. Such complexes are too large to pass the endothelial barrier. The remaining 20 25% of IGFs are bound to other IGFBPs in 40 50 KDa complexes. IGFs are released from IGF:IGFBP complexes by proteolysis of the IGFBP. IGFs become active after release, however IGFs may also have activity when still bound to some IGFBPs. IGFBP1 is enriched in amniotic fluid and is produced in the liver under control of insulin (insulin suppresses production). IGFBP1 binding stimulates IGF function. It is unknown which if any protease degrades IGFBP1. IGFBP2 is enriched in cerebrospinal fluid; its binding inhibits IGF function. IGFBP2 is not significantly degraded in circulation. IGFB3, which binds most IGF in the body is enriched in follicular fluid and found in many other tissues. IGFBP 3 may be cleaved by plasmin, thrombin, Prostate specific Antigen (PSA, KLK3), Matrix Metalloprotease-1 (MMP1), and Matrix Metalloprotease-2 (MMP2). IGFBP3 also binds extracellular matrix and binding lowers its affinity for IGFs. IGFBP3 binding stimulates the effects of IGFs. IGFBP4 acts to inhibit IGF function and is cleaved by Pregnancy associated Plasma Protein A (PAPPA) to release IGF. IGFBP5 is enriched in bone matrix; its binding stimulates IGF function. IGFBP5 is cleaved by Pregnancy Associated Plasma Protein A2 (PAPPA2), ADAM9, complement C1s from smooth muscle, and thrombin. Only the cleavage site for PAPPA2 is known. IGFBP6 is enriched in cerebrospinal fluid. It is unknown which if any protease degrades IGFBP6.

Regulation of TP53 ActivityPathwayR-HSA-5633007 (Reactome) Protein stability and transcriptional activity of TP53 (p53) tumor suppressor are regulated by post-translational modifications that include ubiquitination, phosphorylation, acetylation, methylation, sumoylation and prolyl-isomerization (Kruse and Gu 2009, Meek and Anderson 2009, Santiago et al. 2013, Mantovani et al. 2015). In addition to post-translational modifications, the activity of TP53 is also regulated by binding of transcription co-factors.

In unstressed cells, TP53 protein levels are low due to MDM2-mediated ubiquitination of TP53, which triggers proteasome-mediated degradation. In response to stress, TP53 undergoes stabilizing phosphorylation, mainly at serine residues S15 and S20. Several different kinases can phosphorylate TP53 at