LIN-3/EGF Promotes the Programmed Cell Death of Specific Cells in by Transcriptional Activation of the Pro-apoptotic Gene


Programmed cell death (PCD) is an evolutionarily conserved cellular process that is important for metazoan development and homeostasis. The epidermal growth factor (EGF) promotes cell proliferation, differentiation and survival during animal development. Surprisingly, we found that the EGF-like ligand LIN-3 also promotes the death of specific cells in Caenorhabditis elegans. We found that the LIN-3/EGF signal can be secreted from a cell to facilitate the demise of cells at a distance by activating the transcription of the PCD-promoting gene egl-1 in the doomed cells through the transcription factor LIN-1. LIN-1 binds to the egl-1 promoter in vitro and is positively regulated by the LIN-3/EGF, LET-23/EGF receptor, and the downstream MAPK signaling pathway. To our knowledge, LIN-3/EGF is the first extrinsic signal that has been shown to regulate the intrinsic PCD machinery during C. elegans development. In addition, the transcription factor LIN-31, which binds to LIN-1 and acts downstream of LIN-3/EGF, LET-23/EGF receptor, and the MAPK signaling pathway during vulval development, is dispensable for PCD. Thus, LIN-3/EGF promotes cell proliferation, differentiation, and PCD through common downstream signaling molecules but acts via distinct sets of transcription factors for different target gene expression.


Vyšlo v časopise: LIN-3/EGF Promotes the Programmed Cell Death of Specific Cells in by Transcriptional Activation of the Pro-apoptotic Gene. PLoS Genet 10(8): e32767. doi:10.1371/journal.pgen.1004513
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1004513

Souhrn

Programmed cell death (PCD) is an evolutionarily conserved cellular process that is important for metazoan development and homeostasis. The epidermal growth factor (EGF) promotes cell proliferation, differentiation and survival during animal development. Surprisingly, we found that the EGF-like ligand LIN-3 also promotes the death of specific cells in Caenorhabditis elegans. We found that the LIN-3/EGF signal can be secreted from a cell to facilitate the demise of cells at a distance by activating the transcription of the PCD-promoting gene egl-1 in the doomed cells through the transcription factor LIN-1. LIN-1 binds to the egl-1 promoter in vitro and is positively regulated by the LIN-3/EGF, LET-23/EGF receptor, and the downstream MAPK signaling pathway. To our knowledge, LIN-3/EGF is the first extrinsic signal that has been shown to regulate the intrinsic PCD machinery during C. elegans development. In addition, the transcription factor LIN-31, which binds to LIN-1 and acts downstream of LIN-3/EGF, LET-23/EGF receptor, and the MAPK signaling pathway during vulval development, is dispensable for PCD. Thus, LIN-3/EGF promotes cell proliferation, differentiation, and PCD through common downstream signaling molecules but acts via distinct sets of transcription factors for different target gene expression.


Zdroje

1. FuchsY, StellerH (2011) Programmed cell death in animal development and disease. Cell 147: 742–758.

2. BaehreckeEH (2002) How death shapes life during development. Nat Rev Mol Cell Biol 3: 779–787.

3. LettreG, HengartnerMO (2006) Developmental apoptosis in C. elegans: a complex CEDnario. Nat Rev Mol Cell Biol 7: 97–108.

4. PottsMB, CameronS (2011) Cell lineage and cell death: Caenorhabditis elegans and cancer research. Nat Rev Cancer 11: 50–58.

5. SulstonJE, HorvitzHR (1977) Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 56: 110–156.

6. SulstonJE, SchierenbergE, WhiteJG, ThomsonJN (1983) The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev Biol 100: 64–119.

7. ConradtB, HorvitzHR (1998) The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9. Cell 93: 519–529.

8. HengartnerMO, HorvitzHR (1994) C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76: 665–676.

9. YuanJ, ShahamS, LedouxS, EllisHM, HorvitzHR (1993) The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 75: 641–652.

10. ZouH, HenzelWJ, LiuX, LutschgA, WangX (1997) Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90: 405–413.

11. EllisHM, HorvitzHR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44: 817–829.

12. HengartnerMO, EllisRE, HorvitzHR (1992) Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 356: 494–499.

13. ChenF, HershBM, ConradtB, ZhouZ, RiemerD, et al. (2000) Translocation of C. elegans CED-4 to nuclear membranes during programmed cell death. Science 287: 1485–1489.

14. YanN, GuL, KokelD, ChaiJ, LiW, et al. (2004) Structural, biochemical, and functional analyses of CED-9 recognition by the proapoptotic proteins EGL-1 and CED-4. Mol Cell 15: 999–1006.

15. YangX, ChangHY, BaltimoreD (1998) Essential role of CED-4 oligomerization in CED-3 activation and apoptosis. Science 281: 1355–1357.

16. PourkarimiE, GreissS, GartnerA (2012) Evidence that CED-9/Bcl2 and CED-4/Apaf-1 localization is not consistent with the current model for C. elegans apoptosis induction. Cell Death Differ 19: 406–415.

17. NehmeR, ConradtB (2008) egl-1: a key activator of apoptotic cell death in C. elegans. Oncogene 27 Suppl 1: S30–40.

18. PedenE, KillianDJ, XueD (2008) Cell death specification in C. elegans. Cell Cycle 7: 2479–2484.

19. ThellmannM, HatzoldJ, ConradtB (2003) The Snail-like CES-1 protein of C. elegans can block the expression of the BH3-only cell-death activator gene egl-1 by antagonizing the function of bHLH proteins. Development 130: 4057–4071.

20. GrantS, QiaoL, DentP (2002) Roles of ERBB family receptor tyrosine kinases, and downstream signaling pathways, in the control of cell growth and survival. Front Biosci 7: d376–389.

21. DanielsenAJ, MaihleNJ (2002) The EGF/ErbB receptor family and apoptosis. Growth Factors 20: 1–15.

22. WieduwiltMJ, MoasserMM (2008) The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci 65: 1566–1584.

23. XianCJ, ZhouXF (2004) EGF family of growth factors: essential roles and functional redundancy in the nerve system. Front Biosci 9: 85–92.

24. BergmannA, TugentmanM, ShiloBZ, StellerH (2002) Regulation of cell number by MAPK-dependent control of apoptosis: a mechanism for trophic survival signaling. Dev Cell 2: 159–170.

25. HensonES, GibsonEM, VillanuevaJ, BristowNA, HaneyN, et al. (2003) Increased expression of Mcl-1 is responsible for the blockage of TRAIL-induced apoptosis mediated by EGF/ErbB1 signaling pathway. J Cell Biochem 89: 1177–1192.

26. JostM, HuggettTM, KariC, BoiseLH, RodeckU (2001) Epidermal growth factor receptor-dependent control of keratinocyte survival and Bcl-xL expression through a MEK-dependent pathway. J Biol Chem 276: 6320–6326.

27. LeuCM, ChangC, HuC (2000) Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway. Oncogene 19: 1665–1675.

28. AllanLA, MorriceN, BradyS, MageeG, PathakS, et al. (2003) Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol 5: 647–654.

29. FangX, YuS, EderA, MaoM, BastRCJr, et al. (1999) Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene 18: 6635–6640.

30. GulliLF, PalmerKC, ChenYQ, ReddyKB (1996) Epidermal growth factor-induced apoptosis in A431 cells can be reversed by reducing the tyrosine kinase activity. Cell Growth Differ 7: 173–178.

31. ArmstrongDK, KaufmannSH, OttavianoYL, FuruyaY, BuckleyJA, et al. (1994) Epidermal growth factor-mediated apoptosis of MDA-MB-468 human breast cancer cells. Cancer Res 54: 5280–5283.

32. GarciaR, FranklinRA, McCubreyJA (2006) Cell death of MCF-7 human breast cancer cells induced by EGFR activation in the absence of other growth factors. Cell Cycle 5: 1840–1846.

33. HillRJ, SternbergPW (1992) The gene lin-3 encodes an inductive signal for vulval development in C. elegans. Nature 358: 470–476.

34. AroianRV, KogaM, MendelJE, OhshimaY, SternbergPW (1990) The let-23 gene necessary for Caenorhabditis elegans vulval induction encodes a tyrosine kinase of the EGF receptor subfamily. Nature 348: 693–699.

35. ChamberlinHM, SternbergPW (1994) The lin-3/let-23 pathway mediates inductive signalling during male spicule development in Caenorhabditis elegans. Development 120: 2713–2721.

36. ClandininTR, DeModenaJA, SternbergPW (1998) Inositol trisphosphate mediates a RAS-independent response to LET-23 receptor tyrosine kinase activation in C. elegans. Cell 92: 523–533.

37. JiangLI, SternbergPW (1998) Interactions of EGF, Wnt and HOM-C genes specify the P12 neuroectoblast fate in C. elegans. Development 125: 2337–2347.

38. Van BuskirkC, SternbergPW (2007) Epidermal growth factor signaling induces behavioral quiescence in Caenorhabditis elegans. Nat Neurosci 10: 1300–1307.

39. HanM, SternbergPW (1990) let-60, a gene that specifies cell fates during C. elegans vulval induction, encodes a ras protein. Cell 63: 921–931.

40. ClarkSG, SternMJ, HorvitzHR (1992) C. elegans cell-signalling gene sem-5 encodes a protein with SH2 and SH3 domains. Nature 356: 340–344.

41. HanM, GoldenA, HanY, SternbergPW (1993) C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation. Nature 363: 133–140.

42. WuY, HanM, GuanKL (1995) MEK-2, a Caenorhabditis elegans MAP kinase kinase, functions in Ras-mediated vulval induction and other developmental events. Genes Dev 9: 742–755.

43. KornfeldK, GuanKL, HorvitzHR (1995) The Caenorhabditis elegans gene mek-2 is required for vulval induction and encodes a protein similar to the protein kinase MEK. Genes & Development 9: 756–768.

44. LacknerMR, KornfeldK, MillerLM, HorvitzHR, KimSK (1994) A MAP kinase homolog, mpk-1, is involved in ras-mediated induction of vulval cell fates in Caenorhabditis elegans. Genes & development 8: 160–173.

45. WuY, HanM (1994) Suppression of activated Let-60 ras protein defines a role of Caenorhabditis elegans Sur-1 MAP kinase in vulval differentiation. Genes Dev 8: 147–159.

46. TanPB, LacknerMR, KimSK (1998) MAP kinase signaling specificity mediated by the LIN-1 Ets/LIN-31 WH transcription factor complex during C. elegans vulval induction. Cell 93: 569–580.

47. HopperNA (2006) The adaptor protein soc-1/Gab1 modifies growth factor receptor output in Caenorhabditis elegans. Genetics 173: 163–175.

48. GumiennyTL, LambieE, HartwiegE, HorvitzHR, HengartnerMO (1999) Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline. Development 126: 1011–1022.

49. PerrinAJ, GundaM, YuB, YenK, ItoS, et al. (2013) Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways. Cell Death Differ 20: 97–107.

50. RutkowskiR, DickinsonR, StewartG, CraigA, SchimplM, et al. (2011) Regulation of Caenorhabditis elegans p53/CEP-1-dependent germ cell apoptosis by Ras/MAPK signaling. PLoS Genet 7: e1002238.

51. QuevedoC, KaplanDR, DerryWB (2007) AKT-1 regulates DNA-damage-induced germline apoptosis in C. elegans. Curr Biol 17: 286–292.

52. FergusonEL, HorvitzHR (1985) Identification and characterization of 22 genes that affect the vulval cell lineages of the nematode Caenorhabditis elegans. Genetics 110: 17–72.

53. HoeppnerDJ, HengartnerMO, SchnabelR (2001) Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412: 202–206.

54. EllisRE, JacobsonDM, HorvitzHR (1991) Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans. Genetics 129: 79–94.

55. Hunt-NewburyR, ViveirosR, JohnsenR, MahA, AnastasD, et al. (2007) High-throughput in vivo analysis of gene expression in Caenorhabditis elegans. PLoS Biol 5: e237.

56. ChangC, NewmanAP, SternbergPW (1999) Reciprocal EGF signaling back to the uterus from the induced C. elegans vulva coordinates morphogenesis of epithelia. Curr Biol 9: 237–246.

57. LiuJ, TzouP, HillRJ, SternbergPW (1999) Structural requirements for the tissue-specific and tissue-general functions of the Caenorhabditis elegans epidermal growth factor LIN-3. Genetics 153: 1257–1269.

58. KatzWS, HillRJ, ClandininTR, SternbergPW (1995) Different levels of the C. elegans growth factor LIN-3 promote distinct vulval precursor fates. Cell 82: 297–307.

59. SternbergPW, HorvitzHR (1986) Pattern formation during vulval development in C. elegans. Cell 44: 761–772.

60. HwangBJ, SternbergPW (2004) A cell-specific enhancer that specifies lin-3 expression in the C. elegans anchor cell for vulval development. Development 131: 143–151.

61. FukushigeT, HawkinsMG, McGheeJD (1998) The GATA-factor elt-2 is essential for formation of the Caenorhabditis elegans intestine. Dev Biol 198: 286–302.

62. ConradtB, HorvitzHR (1999) The TRA-1A sex determination protein of C. elegans regulates sexually dimorphic cell deaths by repressing the egl-1 cell death activator gene. Cell 98: 317–327.

63. MillerLM, GallegosME, MorisseauBA, KimSK (1993) lin-31, a Caenorhabditis elegans HNF-3/fork head transcription factor homolog, specifies three alternative cell fates in vulval development. Genes Dev 7: 933–947.

64. BeitelGJ, TuckS, GreenwaldI, HorvitzHR (1995) The Caenorhabditis elegans gene lin-1 encodes an ETS-domain protein and defines a branch of the vulval induction pathway. Genes Dev 9: 3149–3162.

65. MileyGR, FantzD, GlossipD, LuX, SaitoRM, et al. (2004) Identification of residues of the Caenorhabditis elegans LIN-1 ETS domain that are necessary for DNA binding and regulation of vulval cell fates. Genetics 167: 1697–1709.

66. TiensuuT, LarsenMK, VernerssonE, TuckS (2005) lin-1 has both positive and negative functions in specifying multiple cell fates induced by Ras/MAP kinase signaling in C. elegans. Dev Biol 286: 338–351.

67. ChiuB, MirkinB, MadonnaMB (2006) Mitogenic and apoptotic actions of epidermal growth factor on neuroblastoma cells are concentration-dependent. J Surg Res 135: 209–212.

68. WangH, GuoD, YeF, XiG, WangB, et al. (2006) Effect and mechanism of epidermal growth factor on proliferation of GL15 gliomas cell line. J Huazhong Univ Sci Technolog Med Sci 26: 604–606.

69. KileySC, ChevalierRL (2007) Species differences in renal Src activity direct EGF receptor regulation in life or death response to EGF. Am J Physiol Renal Physiol 293: F895–903.

70. SugimotoA, KusanoA, HozakRR, DerryWB, ZhuJ, et al. (2001) Many genomic regions are required for normal embryonic programmed cell death in Caenorhabditis elegans. Genetics 158: 237–252.

71. BooyEP, HensonES, GibsonSB (2011) Epidermal growth factor regulates Mcl-1 expression through the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer. Oncogene 30: 2367–2378.

72. BernsJS, FordPA (1997) Renal toxicities of antineoplastic drugs and bone marrow transplantation. Semin Nephrol 17: 54–66.

73. PricePM, SafirsteinRL, MegyesiJ (2004) Protection of renal cells from cisplatin toxicity by cell cycle inhibitors. Am J Physiol Renal Physiol 286: F378–384.

74. AranyI, MegyesiJK, KanetoH, PricePM, SafirsteinRL (2004) Cisplatin-induced cell death is EGFR/src/ERK signaling dependent in mouse proximal tubule cells. Am J Physiol Renal Physiol 287: F543–549.

75. Frusic-ZlotkinM, RaichenbergD, WangX, DavidM, MichelB, et al. (2006) Apoptotic mechanism in pemphigus autoimmunoglobulins-induced acantholysis–possible involvement of the EGF receptor. Autoimmunity 39: 563–575.

76. BotellaJA, KretzschmarD, KiermayerC, FeldmannP, HughesDA, et al. (2003) Deregulation of the Egfr/Ras signaling pathway induces age-related brain degeneration in the Drosophila mutant vap. Mol Biol Cell 14: 241–250.

77. PaoW, ChmieleckiJ (2010) Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 10: 760–774.

78. BrennerS (1974) The genetics of Caenorhabditis elegans. Genetics 77: 71–94.

79. TimmonsL, CourtDL, FireA (2001) Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans. Gene 263: 103–112.

80. SimmerF, TijstermanM, ParrishS, KoushikaSP, NonetML, et al. (2002) Loss of the putative RNA-directed RNA polymerase RRF-3 makes C. elegans hypersensitive to RNAi. Curr Biol 12: 1317–1319.

81. KamathRS, FraserAG, DongY, PoulinG, DurbinR, et al. (2003) Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421: 231–237.

82. MelloC, FireA (1995) DNA transformation. Methods Cell Biol 48: 451–482.

83. MaduroM, PilgrimD (1995) Identification and cloning of unc-119, a gene expressed in the Caenorhabditis elegans nervous system. Genetics 141: 977–988.

84. SchnabelR, HutterH, MoermanD, SchnabelH (1997) Assessing normal embryogenesis in Caenorhabditis elegans using a 4D microscope: variability of development and regional specification. Dev Biol 184: 234–265.

85. LivakKJ, SchmittgenTD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402–408.

86. GuT, OritaS, HanM (1998) Caenorhabditis elegans SUR-5, a novel but conserved protein, negatively regulates LET-60 Ras activity during vulval induction. Mol Cell Biol 18: 4556–4564.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2014 Číslo 8
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz

Betablokátory a Ca antagonisté z jiného úhlu
Autori: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Autori: doc. MUDr. Petr Čáp, Ph.D.

Farmakoterapie akutní a chronické bolesti

Získaná hemofilie - Povědomí o nemoci a její diagnostika

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa