Skip to main content
Log in

Crossing paths: interactions between the cell death machinery and growth factor survival signals

  • Multi-author Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Cytokines and growth factors play a crucial role in the maintenance of haematopoietic homeostasis. They transduce signals that regulate the competing commitments of haematopoietic stem cells, quiescence or proliferation, retention of stem cell pluripotency or differentiation, and survival or demise. When the balance between these commitments and the requirements of the organisms is disturbed, particularly when it favours survival and proliferation, cancer may result. Cell death provoked by loss of growth factor signalling is regulated by the Bcl-2 family of apoptosis regulators, and thus survival messages transduced by growth factors must regulate the activity of these proteins. Many aspects of direct interactions between cytokine signalling and regulation of apoptosis remain elusive. In this review, we explore the mechanisms by which cytokines, in particular Interleukin-3 and granulocyte–macrophage colony-stimulating factor, promote cell survival and suppress apoptosis as models of how cytokine signalling and apoptotic pathways intersect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF (1999) Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction. Cell 98:181–191

    Article  CAS  PubMed  Google Scholar 

  2. Suzuki N, Ohneda O, Takahashi S, Higuchi M, Mukai HY, Nakahata T, Imagawa S, Yamamoto M (2002) Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality. Blood 100:2279–2288

    Article  CAS  PubMed  Google Scholar 

  3. Wu H, Klingmuller U, Acurio A, Hsiao JG, Lodish HF (1997) Functional interaction of erythropoietin and stem cell factor receptors is essential for erythroid colony formation. Proc Natl Acad Sci USA 94:1806–1810

    Article  CAS  PubMed  Google Scholar 

  4. Stanley E, Lieschke GJ, Grail D, Metcalf D, Hodgson G, Gall JA, Maher DW, Cebon J, Sinickas V, Dunn AR (1994) Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci USA 91:5592–5596

    Article  CAS  PubMed  Google Scholar 

  5. Dranoff G, Mulligan RC (1994) Activities of granulocyte-macrophage colony-stimulating factor revealed by gene transfer and gene knockout studies. Stem Cells 12:173–182

    PubMed  Google Scholar 

  6. Metcalf D (1980) Clonal analysis of proliferation and differentiation of paired daughter cells: action of granulocyte-macrophage colony-stimulating factor on granulocyte-macrophage precursors. Proc Natl Acad Sci USA 77:5327–5330

    Article  CAS  PubMed  Google Scholar 

  7. Metcalf D (1991) Transgenic mice as models of hemopoiesis. Cancer 67:2695–2699

    Article  CAS  PubMed  Google Scholar 

  8. Nishinakamura R, Miyajima A, Mee PJ, Tybulewicz VL, Murray R (1996) Hematopoiesis in mice lacking the entire granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 functions. Blood 88:2458–2464

    CAS  PubMed  Google Scholar 

  9. Tsujimoto Y, Cossman J, Jaffe E, Croce CM (1985) Involvement of the bcl-2 gene in human follicular lymphoma. Science 228:1440–1443

    Article  CAS  PubMed  Google Scholar 

  10. Kindler V, Thorens B, de Kossodo S, Allet B, Eliason JF, Thatcher D, Farber N, Vassalli P (1986) Stimulation of hematopoiesis in vivo by recombinant bacterial murine interleukin 3. Proc Natl Acad Sci USA 83:1001–1005

    Article  CAS  PubMed  Google Scholar 

  11. Saeland S, Caux C, Favre C, Aubry JP, Mannoni P, Pebusque MJ, Gentilhomme O, Otsuka T, Yokota T, Arai N (1988) Effects of recombinant human interleukin-3 on CD34-enriched normal hematopoietic progenitors and on myeloblastic leukemia cells. Blood 72:1580–1588

    CAS  PubMed  Google Scholar 

  12. Dan Y, Katakura Y, Ametani A, Kaminogawa S, Asano Y (1996) IL-3 augments TCR-mediated responses of type 2 CD4 T cells. J Immunol 156:27–34

    CAS  PubMed  Google Scholar 

  13. Nishinakamura R, Nakayama N, Hirabayashi Y, Inoue T, Aud D, McNeil T, Azuma S, Yoshida S, Toyoda Y, Arai K (1995) Mice deficient for the IL-3/GM-CSF/IL-5 beta c receptor exhibit lung pathology and impaired immune response, while beta IL3 receptor-deficient mice are normal. Immunity 2:211–222

    Article  CAS  PubMed  Google Scholar 

  14. Schwarze J, Cieslewicz G, Hamelmann E, Joetham A, Shultz LD, Lamers MC, Gelfand EW (1999) IL-5 and eosinophils are essential for the development of airway hyperresponsiveness following acute respiratory syncytial virus infection. J Immunol 162:2997–3004

    CAS  PubMed  Google Scholar 

  15. Yamaguchi Y, Suda T, Suda J, Eguchi M, Miura Y, Harada N, Tominaga A, Takatsu K (1988) Purified interleukin 5 supports the terminal differentiation and proliferation of murine eosinophilic precursors. J Exp Med 167:43–56

    Article  CAS  PubMed  Google Scholar 

  16. Guthridge MA, Stomski FC, Thomas D, Woodcock JM, Bagley CJ, Berndt MC, Lopez AF (1998) Mechanism of activation of the GM-CSF, IL-3, and IL-5 family of receptors. Stem Cells 16:301–313

    Article  CAS  PubMed  Google Scholar 

  17. Robb L (2007) Cytokine receptors and hematopoietic differentiation. Oncogene 26:6715–6723

    Article  CAS  PubMed  Google Scholar 

  18. Hansen G, Hercus TR, McClure BJ, Stomski FC, Dottore M, Powell J, Ramshaw H, Woodcock JM, Xu Y, Guthridge M, McKinstry WJ, Lopez AF, Parker MW (2008) The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell 134:496–507

    Article  CAS  PubMed  Google Scholar 

  19. Hercus TR, Thomas D, Guthridge MA, Ekert PG, King-Scott J, Parker MW, Lopez AF (2009) The GM-CSF receptor: linking its structure to cell signaling and its role in disease. Blood 114:1289–1298

    Article  CAS  PubMed  Google Scholar 

  20. Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, Vanin EF, Bodner S, Colamonici OR, van Deursen JM, Grosveld G, Ihle JN (1998) Jak2 is essential for signaling through a variety of cytokine receptors. Cell 93:385–395

    Article  CAS  PubMed  Google Scholar 

  21. Quelle FW, Sato N, Witthuhn BA, Inhorn RC, Eder M, Miyajima A, Griffin JD, Ihle JN (1994) JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region. Mol Cell Biol 14:4335–4341

    CAS  PubMed  Google Scholar 

  22. Dirksen U, Nishinakamura R, Groneck P, Hattenhorst U, Nogee L, Murray R, Burdach S (1997) JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region. J Clin Invest 100:2211–2217

    Article  CAS  PubMed  Google Scholar 

  23. Martinez-Moczygemba M, Doan ML, Elidemir O, Fan LL, Cheung SW, Lei JT, Moore JP, Tavana G, Lewis LR, Zhu Y, Muzny DM, Gibbs RA, Huston DP (2008) Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRalpha gene in the X chromosome pseudoautosomal region 1. J Exp Med 205:2711–2716

    Article  CAS  PubMed  Google Scholar 

  24. Metcalf D, Robb L, Dunn AR, Mifsud S, Di Rago L (1996) Role of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in the development of an acute neutrophil inflammatory response in mice. Blood 88:3755–3764

    CAS  PubMed  Google Scholar 

  25. Ravandi F (2006) Role of cytokines in the treatment of acute leukemias: a review. Leukemia 20:563–571

    Article  CAS  PubMed  Google Scholar 

  26. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  27. Testa U, Riccioni R, Militi S, Coccia E, Stellacci E, Samoggia P, Latagliata R, Mariani G, Rossini A, Battistini A, Lo-Coco F, Peschle C (2002) Elevated expression of IL-3Ralpha in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis. Blood 100:2980–2988

    Article  CAS  PubMed  Google Scholar 

  28. Testa U, Riccioni R, Diverio D, Rossini A, Lo Coco F, Peschle C (2004) Interleukin-3 receptor in acute leukemia. Leukemia 18:219–226

    Article  CAS  PubMed  Google Scholar 

  29. Perkins A, Kongsuwan K, Visvader J, Adams JM, Cory S (1990) Homeobox gene expression plus autocrine growth factor production elicits myeloid leukemia. Proc Natl Acad Sci USA 87:8398–8402

    Article  CAS  PubMed  Google Scholar 

  30. Hasle H (2007) Myelodysplastic and myeloproliferative disorders in children. Curr Opin Pediatr 19:1–8

    Article  PubMed  Google Scholar 

  31. Emanuel PD, Bates LJ, Castleberry RP, Gualtieri RJ, Zuckerman KS (1991) Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 77:925–929

    CAS  PubMed  Google Scholar 

  32. Chan RJ, Leedy MB, Munugalavadla V, Voorhorst CS, Li Y, Yu M, Kapur R (2005) Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood 105:3737–3742

    Article  CAS  PubMed  Google Scholar 

  33. Jiang X, Lopez A, Holyoake T, Eaves A, Eaves C (1999) Autocrine production and action of IL-3 and granulocyte colony-stimulating factor in chronic myeloid leukemia. Proc Natl Acad Sci USA 96:12804–12809

    Article  CAS  PubMed  Google Scholar 

  34. Gualtieri RJ, Emanuel PD, Zuckerman KS, Martin G, Clark SC, Shadduck RK, Dracker RA, Akabutu J, Nitschke R, Hetherington ML, Dickerman JD, Hakami N, Castleberry RP (1989) Granulocyte-macrophage colony-stimulating factor is an endogenous regulator of cell proliferation in juvenile chronic myelogenous leukemia. Blood 74:2360–2367

    CAS  PubMed  Google Scholar 

  35. Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM (1984) Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226:1097–1099

    Article  CAS  PubMed  Google Scholar 

  36. Dexter TM, Garland J, Scott D, Scolnick E, Metcalf D (1980) Growth of factor-dependent hemopoietic precursor cell lines. J Exp Med 152:1036–1047

    Article  CAS  PubMed  Google Scholar 

  37. Hariharan IK, Adams JM, Cory S (1988) bcr-abl oncogene renders myeloid cell line factor independent: potential autocrine mechanism in chronic myeloid leukemia. Oncogene Res 3:387–399

    CAS  PubMed  Google Scholar 

  38. Vaux DL, Cory S, Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335:440–442

    Article  CAS  PubMed  Google Scholar 

  39. Vaux DL, Aguila HL, Weissman IL (1992) Bcl-2 prevents death of factor-deprived cells but fails to prevent apoptosis in targets of cell mediated killing. Int Immunol 4:821–824

    Article  CAS  PubMed  Google Scholar 

  40. Chen Q, Takeyama N, Brady G, Watson AJ, Dive C (1998) Blood cells with reduced mitochondrial membrane potential and cytosolic cytochrome C can survive and maintain clonogenicity given appropriate signals to suppress apoptosis. Blood 92:4545–4553

    CAS  PubMed  Google Scholar 

  41. Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656

    Article  CAS  PubMed  Google Scholar 

  42. Nechushtan A, Smith CL, Lamensdorf I, Yoon SH, Youle RJ (2001) Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. J Cell Biol 153:1265–1276

    Article  CAS  PubMed  Google Scholar 

  43. Nechushtan A, Smith CL, Hsu YT, Youle RJ (1999) Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J 18:2330–2341

    Article  CAS  PubMed  Google Scholar 

  44. Griffiths GJ, Dubrez L, Morgan CP, Jones NA, Whitehouse J, Corfe BM, Dive C, Hickman JA (1999) Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis. J Cell Biol 144:903–914

    Article  CAS  PubMed  Google Scholar 

  45. Annis MG, Soucie EL, Dlugosz PJ, Cruz-Aguado JA, Penn LZ, Leber B, Andrews DW (2005) Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis. EMBO J 24:2096–2103

    Article  CAS  PubMed  Google Scholar 

  46. Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD (2005) BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17:525–535

    Article  CAS  PubMed  Google Scholar 

  47. Lovell JF, Billen LP, Bindner S, Shamas-Din A, Fradin C, Leber B, Andrews DW (2008) Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell 135:1074–1084

    Article  CAS  PubMed  Google Scholar 

  48. Gross A, Jockel J, Wei MC, Korsmeyer SJ (1998) Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J 17:3878–3885

    Article  CAS  PubMed  Google Scholar 

  49. Low W, Olmos-Centenera G, Madsen C, Leverrier Y, Collins MK (2001) Role of Bax in apoptosis of IL-3-dependent cells. Oncogene 20:4476–4483

    Article  CAS  PubMed  Google Scholar 

  50. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730

    Article  CAS  PubMed  Google Scholar 

  51. Ekert PG, Jabbour AM, Manoharan A, Heraud JE, Yu J, Pakusch M, Michalak EM, Kelly PN, Callus B, Kiefer T, Verhagen A, Silke J, Strasser A, Borner C, Vaux DL (2006) Cell death provoked by loss of interleukin-3 signaling is independent of Bad, Bim, and PI3 kinase, but depends in part on Puma. Blood 108:1461–1468

    Article  CAS  PubMed  Google Scholar 

  52. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75:229–240

    Article  CAS  PubMed  Google Scholar 

  53. Gonzalez-Garcia M, Garcia I, Ding L, O’Shea S, Boise LH, Thompson CB, Nunez G (1995) bcl-x is expressed in embryonic and postnatal neural tissues and functions to prevent neuronal cell death. Proc Natl Acad Sci USA 92:4304–4308

    Article  CAS  PubMed  Google Scholar 

  54. Motoyama N, Wang F, Roth KA, Sawa H, Nakayama K, Nakayama K, Negishi I, Senju S, Zhang Q, Fujii S, Loh DY (1995) Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267:1506–1510

    Article  CAS  PubMed  Google Scholar 

  55. Rinkenberger JL, Horning S, Klocke B, Roth K, Korsmeyer SJ (2000) Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev 14:23–27

    CAS  PubMed  Google Scholar 

  56. Ross AJ, Waymire KG, Moss JE, Parlow AF, Skinner MK, Russell LD, MacGregor GR (1998) Testicular degeneration in Bclw-deficient mice. Nat Genet 18:251–256

    Article  CAS  PubMed  Google Scholar 

  57. Hamasaki A, Sendo F, Nakayama K, Ishida N, Negishi I, Nakayama K, Hatakeyama S (1998) Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the bcl-2-related A1 gene. J Exp Med 188:1985–1992

    Article  CAS  PubMed  Google Scholar 

  58. Klampfer L, Zhang J, Nimer SD (1999) GM-CSF rescues TF-1 cells from growth factor withdrawal-induced, but not differentiation-induced apoptosis: the role of BCL-2 and MCL-1. Cytokine 11:849–855

    Article  CAS  PubMed  Google Scholar 

  59. Rinaudo MS, Su K, Falk LA, Halder S, Mufson RA (1995) Human interleukin-3 receptor modulates bcl-2 mRNA and protein levels through protein kinase C in TF-1 cells. Blood 86:80–88

    CAS  PubMed  Google Scholar 

  60. Chao JR, Wang JM, Lee SF, Peng HW, Lin YH, Chou CH, Li JC, Huang HM, Chou CK, Kuo ML, Yen JJ, Yang-Yen HF (1998) Mcl-1 is an immediate-early gene activated by the granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling pathway and is one component of the GM-CSF viability response. Mol Cell Biol 18:4883–4898

    CAS  PubMed  Google Scholar 

  61. Moulding DA, Quayle JA, Hart CA, Edwards SW (1998) Mcl-1 expression in human neutrophils: regulation by cytokines and correlation with cell survival. Blood 92:2495–2502

    CAS  PubMed  Google Scholar 

  62. Derouet M, Thomas L, Cross A, Moots RJ, Edwards SW (2004) Granulocyte macrophage colony-stimulating factor signaling and proteasome inhibition delay neutrophil apoptosis by increasing the stability of Mcl-1. J Biol Chem 279:26915–26921

    Article  CAS  PubMed  Google Scholar 

  63. Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR (2006) Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21:749–760

    Article  CAS  PubMed  Google Scholar 

  64. Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC (2005) Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 19:1294–1305

    Article  CAS  PubMed  Google Scholar 

  65. Lee EF, Czabotar PE, van Delft MF, Michalak EM, Boyle MJ, Willis SN, Puthalakath H, Bouillet P, Colman PM, Huang DC, Fairlie WD (2008) A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation. J Cell Biol 180:341–355

    Article  CAS  PubMed  Google Scholar 

  66. Poommipanit PB, Chen B, Oltvai ZN (1999) Interleukin-3 induces the phosphorylation of a distinct fraction of bcl-2. J Biol Chem 274:1033–1039

    Article  CAS  PubMed  Google Scholar 

  67. Ruvolo PP, Deng X, May WS (2001) Phosphorylation of Bcl2 and regulation of apoptosis. Leukemia 15:515–522

    Article  CAS  PubMed  Google Scholar 

  68. Deng X, Ruvolo P, Carr B, May WS Jr (2000) Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases. Proc Natl Acad Sci USA 97:1578–1583

    Article  CAS  PubMed  Google Scholar 

  69. Kuroda J, Puthalakath H, Cragg MS, Kelly PN, Bouillet P, Huang DC, Kimura S, Ottmann OG, Druker BJ, Villunger A, Roberts AW, Strasser A (2006) Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proc Natl Acad Sci USA 103:14907–14912

    Article  CAS  PubMed  Google Scholar 

  70. Erlacher M, Michalak EM, Kelly PN, Labi V, Niederegger H, Coultas L, Adams JM, Strasser A, Villunger A (2005) BH3-only proteins Puma and Bim are rate-limiting for gamma-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo. Blood 106:4131–4138

    Article  CAS  PubMed  Google Scholar 

  71. Kaufmann T, Jost PJ, Pellegrini M, Puthalakath H, Gugasyan R, Gerondakis S, Cretney E, Smyth MJ, Silke J, Hakem R, Bouillet P, Mak TW, Dixit VM, Strasser A (2009) Fatal hepatitis mediated by tumor necrosis factor TNFalpha requires caspase-8 and involves the BH3-only proteins Bid and Bim. Immunity 30:56–66

    Article  CAS  PubMed  Google Scholar 

  72. Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, Adams JM, Strasser A (1999) Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286:1735–1738

    Article  CAS  PubMed  Google Scholar 

  73. Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (2005) Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17:393–403

    Article  CAS  PubMed  Google Scholar 

  74. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87:619–628

    Article  CAS  PubMed  Google Scholar 

  75. Zha J, Harada H, Osipov K, Jockel J, Waksman G, Korsmeyer SJ (1997) BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity. J Biol Chem 272:24101–24104

    Article  CAS  PubMed  Google Scholar 

  76. Egle A, Harris AW, Bouillet P, Cory S (2004) Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci USA 101:6164–6169

    Article  CAS  PubMed  Google Scholar 

  77. Bosque A, Marzo I, Naval J, Anel A (2007) Apoptosis by IL-2 deprivation in human CD8+ T cell blasts predominates over death receptor ligation, requires Bim expression and is associated with Mcl-1 loss. Mol Immunol 44:1446–1453

    Article  CAS  PubMed  Google Scholar 

  78. You H, Pellegrini M, Tsuchihara K, Yamamoto K, Hacker G, Erlacher M, Villunger A, Mak TW (2006) FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal. J Exp Med 203:1657–1663

    Article  CAS  PubMed  Google Scholar 

  79. Alfredsson J, Puthalakath H, Martin H, Strasser A, Nilsson G (2005) Proapoptotic Bcl-2 family member Bim is involved in the control of mast cell survival and is induced together with Bcl-XL upon IgE-receptor activation. Cell Death Differ 12:136–144

    Article  CAS  PubMed  Google Scholar 

  80. Whitfield J, Neame SJ, Paquet L, Bernard O, Ham J (2001) Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. Neuron 29:629–643

    Article  CAS  PubMed  Google Scholar 

  81. Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ (2000) Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 10:1201–1204

    Article  CAS  PubMed  Google Scholar 

  82. Stahl M, Dijkers PF, Kops GJ, Lens SM, Coffer PJ, Burgering BM, Medema RH (2002) The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol 168:5024–5031

    CAS  PubMed  Google Scholar 

  83. Ekoff M, Kaufmann T, Engstrom M, Motoyama N, Villunger A, Jonsson JI, Strasser A, Nilsson G (2007) The BH3-only protein Puma plays an essential role in cytokine deprivation induced apoptosis of mast cells. Blood 110:3209–3217

    Article  CAS  PubMed  Google Scholar 

  84. Puthalakath H, Huang DC, O’Reilly LA, King SM, Strasser A (1999) The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 3:287–296

    Article  CAS  PubMed  Google Scholar 

  85. Qi XJ, Wildey GM, Howe PH (2006) Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. J Biol Chem 281:813–823

    Article  CAS  PubMed  Google Scholar 

  86. Hubner A, Barrett T, Flavell RA, Davis RJ (2008) Multisite phosphorylation regulates Bim stability and apoptotic activity. Mol Cell 30:415–425

    Article  CAS  PubMed  Google Scholar 

  87. Jeffers JR, Parganas E, Lee Y, Yang C, Wang J, Brennan J, MacLean KH, Han J, Chittenden T, Ihle JN, McKinnon PJ, Cleveland JL, Zambetti GP (2003) Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4:321–328

    Article  CAS  PubMed  Google Scholar 

  88. Villunger A, Michalak EM, Coultas L, Mullauer F, Bock G, Ausserlechner MJ, Adams JM, Strasser A (2003) p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302:1036–1038

    Article  CAS  PubMed  Google Scholar 

  89. Zhao Y, Coloff JL, Ferguson EC, Jacobs SR, Cui K, Rathmell JC (2008) Glucose metabolism attenuates p53 and Puma-dependent cell death upon growth factor deprivation. J Biol Chem 283:36344–36353

    Article  CAS  PubMed  Google Scholar 

  90. Jabbour AM, Heraud JE, Daunt CP, Kaufmann T, Sandow J, O’Reilly LA, Callus BA, Lopez A, Strasser A, Vaux DL, Ekert PG (2009) Puma indirectly activates Bax to cause apoptosis in the absence of Bid or Bim. Cell Death Differ 16:555–563

    Article  CAS  PubMed  Google Scholar 

  91. Lotem J, Sachs L (1997) Cytokine suppression of protease activation in wild-type p53-dependent and p53-independent apoptosis. Proc Natl Acad Sci USA 94:9349–9353

    Article  CAS  PubMed  Google Scholar 

  92. Nakano K, Vousden KH (2001) PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 7:683–694

    Article  CAS  PubMed  Google Scholar 

  93. Zhao Y, Wagner F, Frank SJ, Kraft AS (1995) The amino-terminal portion of the JAK2 protein kinase is necessary for binding and phosphorylation of the granulocyte-macrophage colony-stimulating factor receptor beta c chain. J Biol Chem 270:13814–13818

    Article  CAS  PubMed  Google Scholar 

  94. Watanabe S, Itoh T, Arai K (1996) JAK2 is essential for activation of c-fos and c-myc promoters and cell proliferation through the human granulocyte-macrophage colony-stimulating factor receptor in BA/F3 cells. J Biol Chem 271:12681–12686

    Article  CAS  PubMed  Google Scholar 

  95. Jenkins BJ, Blake TJ, Gonda TJ (1998) Saturation mutagenesis of the beta subunit of the human granulocyte-macrophage colony-stimulating factor receptor shows clustering of constitutive mutations, activation of ERK MAP kinase and STAT pathways, and differential beta subunit tyrosine phosphorylation. Blood 92:1989–2002

    CAS  PubMed  Google Scholar 

  96. Inhorn RC, Carlesso N, Durstin M, Frank DA, Griffin JD (1995) Identification of a viability domain in the granulocyte/macrophage colony-stimulating factor receptor beta-chain involving tyrosine-750. Proc Natl Acad Sci USA 92:8665–8669

    Article  CAS  PubMed  Google Scholar 

  97. Sakamaki K, Miyajima I, Kitamura T, Miyajima A (1992) Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation. EMBO J 11:3541–3549

    CAS  PubMed  Google Scholar 

  98. Polotskaya A, Zhao Y, Lilly MB, Kraft AS (1994) Mapping the intracytoplasmic regions of the alpha granulocyte-macrophage colony-stimulating factor receptor necessary for cell growth regulation. J Biol Chem 269:14607–14613

    CAS  PubMed  Google Scholar 

  99. Brown AL, Peters M, D’Andrea RJ, Gonda TJ (2004) Constitutive mutants of the GM-CSF receptor reveal multiple pathways leading to myeloid cell survival, proliferation, and granulocyte-macrophage differentiation. Blood 103:507–516

    Article  CAS  PubMed  Google Scholar 

  100. Itoh T, Liu R, Yokota T, Arai KI, Watanabe S (1998) Definition of the role of tyrosine residues of the common beta subunit regulating multiple signaling pathways of granulocyte-macrophage colony-stimulating factor receptor. Mol Cell Biol 18:742–752

    CAS  PubMed  Google Scholar 

  101. Kieslinger M, Woldman I, Moriggl R, Hofmann J, Marine JC, Ihle JN, Beug H, Decker T (2000) Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation. Genes Dev 14:232–244

    CAS  PubMed  Google Scholar 

  102. Mui AL, Wakao H, Kinoshita T, Kitamura T, Miyajima A (1996) Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5, role of Stat5 in proliferation. EMBO J 15:2425–2433

    CAS  PubMed  Google Scholar 

  103. Dumon S, Santos SC, Debierre-Grockiego F, Gouilleux-Gruart V, Cocault L, Boucheron C, Mollat P, Gisselbrecht S, Gouilleux F (1999) IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line. Oncogene 18:4191–4199

    Article  CAS  PubMed  Google Scholar 

  104. Stout BA, Bates ME, Liu LY, Farrington NN, Bertics PJ (2004) IL-5 and granulocyte-macrophage colony-stimulating factor activate STAT3 and STAT5 and promote Pim-1 and cyclin D3 protein expression in human eosinophils. J Immunol 173:6409–6417

    CAS  PubMed  Google Scholar 

  105. Amson R, Sigaux F, Przedborski S, Flandrin G, Givol D, Telerman A (1989) The human protooncogene product p33pim is expressed during fetal hematopoiesis and in diverse leukemias. Proc Natl Acad Sci USA 86:8857–8861

    Article  CAS  PubMed  Google Scholar 

  106. Amaravadi R, Thompson CB (2005) The survival kinases Akt and Pim as potential pharmacological targets. J Clin Invest 115:2618–2624

    Article  CAS  PubMed  Google Scholar 

  107. Fox CJ, Hammerman PS, Cinalli RM, Master SR, Chodosh LA, Thompson CB (2003) The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev 17:1841–1854

    Article  CAS  PubMed  Google Scholar 

  108. Yan B, Zemskova M, Holder S, Chin V, Kraft A, Koskinen PJ, Lilly M (2003) The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death. J Biol Chem 278:45358–45367

    Article  CAS  PubMed  Google Scholar 

  109. Hammerman PS, Fox CJ, Cinalli RM, Xu A, Wagner JD, Lindsten T, Thompson CB (2004) Lymphocyte transformation by Pim-2 is dependent on nuclear factor-kappaB activation. Cancer Res 64:8341–8348

    Article  CAS  PubMed  Google Scholar 

  110. Banerjee A, Grumont R, Gugasyan R, White C, Strasser A, Gerondakis S (2008) NF-kappaB1 and c-Rel cooperate to promote the survival of TLR4-activated B cells by neutralizing Bim via distinct mechanisms. Blood 112:5063–5073

    Article  CAS  PubMed  Google Scholar 

  111. Aho TL, Sandholm J, Peltola KJ, Mankonen HP, Lilly M, Koskinen PJ (2004) Pim-1 kinase promotes inactivation of the pro-apoptotic Bad protein by phosphorylating it on the Ser112 gatekeeper site. FEBS Lett 571:43–49

    Article  CAS  PubMed  Google Scholar 

  112. Didichenko SA, Spiegl N, Brunner T, Dahinden CA (2008) IL-3 induces a Pim1-dependent antiapoptotic pathway in primary human basophils. Blood 112:3949–3958

    Article  CAS  PubMed  Google Scholar 

  113. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501

    Article  CAS  PubMed  Google Scholar 

  114. Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME (1997) Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275:661–665

    Article  CAS  PubMed  Google Scholar 

  115. Tamburini J, Elie C, Bardet V, Chapuis N, Park S, Broët P, Cornillet-Lefebvre P, Lioure B, Ugo V, Blanchet O, Ifrah N, Witz F, Dreyfus F, Mayeux P, Lacombe C, Bouscary D (2007) Blood 110:1025–1028

    Google Scholar 

  116. Edinger AL, Thompson CB (2002) Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell 13:2276–2288

    Article  CAS  PubMed  Google Scholar 

  117. Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM, Thompson CB (2003) Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol Cell Biol 23:7315–7328

    Article  CAS  PubMed  Google Scholar 

  118. Terada K, Kaziro Y, Satoh T (1995) Ras is not required for the interleukin 3-induced proliferation of a mouse pro-B cell line, BaF3. J Biol Chem 270:27880–27886

    Article  CAS  PubMed  Google Scholar 

  119. Perkins GR, Marshall CJ, Collins MK (1996) The role of MAP kinase kinase in interleukin-3 stimulation of proliferation. Blood 87:3669–3675

    CAS  PubMed  Google Scholar 

  120. Ewings KE, Hadfield-Moorhouse K, Wiggins CM, Wickenden JA, Balmanno K, Gilley R, Degenhardt K, White E, Cook SJ (2007) ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL. EMBO J 26:2856–2867

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gabriela Brumatti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brumatti, G., Salmanidis, M. & Ekert, P.G. Crossing paths: interactions between the cell death machinery and growth factor survival signals. Cell. Mol. Life Sci. 67, 1619–1630 (2010). https://doi.org/10.1007/s00018-010-0288-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-010-0288-8

Keywords

Navigation