Antagonistic Regulation of Apoptosis and Differentiation by the Cut Transcription Factor Represents a Tumor-Suppressing Mechanism in

English version České info

Apoptosis is essential to prevent oncogenic transformation by triggering self-destruction of harmful cells, including those unable to differentiate. However, the mechanisms linking impaired cell differentiation and apoptosis during development and disease are not well understood. Here we report that the Drosophila transcription factor Cut coordinately controls differentiation and repression of apoptosis via direct regulation of the pro-apoptotic gene reaper. We also demonstrate that this regulatory circuit acts in diverse cell lineages to remove uncommitted precursor cells in status nascendi and thereby interferes with their potential to develop into cancer cells. Consistent with the role of Cut homologues in controlling cell death in vertebrates, we find repression of apoptosis regulators by Cux1 in human cancer cells. Finally, we present evidence that suggests that other lineage-restricted specification factors employ a similar mechanism to put the brakes on the oncogenic process.

Vyšlo v časopise: Antagonistic Regulation of Apoptosis and Differentiation by the Cut Transcription Factor Represents a Tumor-Suppressing Mechanism in. PLoS Genet 8(3): e32767. doi:10.1371/journal.pgen.1002582
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002582

Souhrn

Zdroje

1. HanahanDWeinbergRA 2000 The hallmarks of cancer. Cell 100 57 70

2. HarrisH 2005 A long view of fashions in cancer research. Bioessays 27 833 838

3. ShahNSukumarS 2010 The Hox genes and their roles in oncogenesis. Nat Rev Cancer 10 361 370

4. BossuytWDe GeestNAertsSLeenaertsIMarynenP 2009 The Atonal proneural transcription factor links differentiation and tumor formation in Drosophila. PLoS Biol 7 e40 doi:10.1371/journal.pbio.1000040

5. VidalMCaganRL 2006 Drosophila models for cancer research. Curr Opin Genet Dev 16 10 16

6. PorttLNormanGClappCGreenwoodMGreenwoodMT 2011 Anti-apoptosis and cell survival: A review. Biochim Biophys Acta

7. PitsouliCPerrimonN 2010 Embryonic multipotent progenitors remodel the Drosophila airways during metamorphosis. Development 137 3615 3624

8. WerzCLeeTVLeePLLackeyMBolducC 2005 Mis-specified cells die by an active gene-directed process, and inhibition of this death results in cell fate transformation in Drosophila. Development 132 5343 5352

9. HuNCastelli-GairJ 1999 Study of the posterior spiracles of Drosophila as a model to understand the genetic and cellular mechanisms controlling morphogenesis. Dev Biol 214 197 210

10. GoyalLMcCallKAgapiteJHartwiegEStellerH 2000 Induction of apoptosis by Drosophila reaper, hid and grim through inhibition of IAP function. EMBO J 19 589 597

11. BardetPLKolahgarGMynettAMiguel-AliagaIBriscoeJ 2008 A fluorescent reporter of caspase activity for live imaging. Proc Natl Acad Sci U S A 105 13901 13905

12. HayBAWolffTRubinGM 1994 Expression of baculovirus P35 prevents cell death in Drosophila. Development 120 2121 2129

13. MerabetSCatalaFPradelJGrabaY 2002 A green fluorescent protein reporter genetic screen that identifies modifiers of Hox gene function in the Drosophila embryo. Genetics 162 189 202

14. NepveuA 2001 Role of the multifunctional CDP/Cut/Cux homeodomain transcription factor in regulating differentiation, cell growth and development. Gene 270 1 15

15. HilgersVBushatiNCohenSM Drosophila microRNAs 263a/b confer robustness during development by protecting nascent sense organs from apoptosis. PLoS Biol 8 e1000396 doi:10.1371/journal.pbio.1000396

16. Ferres-MarcoDGutierrez-GarciaIVallejoDMBolivarJGutierrez-AvinoFJ 2006 Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439 430 436

17. PalomeroTSulisMLCortinaMRealPJBarnesK 2007 Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 13 1203 1210

18. WilleckeMToggweilerJBaslerK Loss of PI3K blocks cell-cycle progression in a Drosophila tumor model. Oncogene 30 4067 4074

19. PagliariniRAXuT 2003 A genetic screen in Drosophila for metastatic behavior. Science 302 1227 1231

20. MohametLHawkinsKWardCM 2011 Loss of function of E-cadherin in embryonic stem cells and the relevance to models of tumorigenesis. J Oncol 2011 352616

21. BokelCBrownNH 2002 Integrins in development: moving on, responding to, and sticking to the extracellular matrix. Dev Cell 3 311 321

22. ChafferCLWeinbergRA 2011 A perspective on cancer cell metastasis. Science 331 1559 1564

23. SansregretLNepveuA 2008 The multiple roles of CUX1: insights from mouse models and cell-based assays. Gene 412 84 94

24. QuagginSEYegerHIgarashiP 1997 Antisense oligonucleotides to Cux-1, a Cut-related homeobox gene, cause increased apoptosis in mouse embryonic kidney cultures. J Clin Invest 99 718 724

25. RipkaSNeesseARiedelJBugEAignerA 2010 CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic cancer. Gut 59 1101 1110

26. SinclairAMLeeJAGoldsteinAXingDLiuS 2001 Lymphoid apoptosis and myeloid hyperplasia in CCAAT displacement protein mutant mice. Blood 98 3658 3667

27. WoodhouseECLiottaLA 2004 Drosophila invasive tumors: a model for understanding metastasis. Cell Cycle 3 38 40

28. YuJWangPMingLWoodMAZhangL 2007 SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events. Oncogene 26 4189 4198

29. ZhouLSchnitzlerAAgapiteJSchwartzLMStellerH 1997 Cooperative functions of the reaper and head involution defective genes in the programmed cell death of Drosophila central nervous system midline cells. Proc Natl Acad Sci U S A 94 5131 5136

30. Portales-CasamarEThongjueaSKwonATArenillasDZhaoX 2010 JASPAR 2010: the greatly expanded open-access database of transcription factor binding profiles. Nucleic Acids Res 38 D105 110

31. CertelKAndersonMGShrigleyRJJohnsonWA 1996 Distinct variant DNA-binding sites determine cell-specific autoregulated expression of the Drosophila POU domain transcription factor Drifter in midline glia or trachea. Mol Cell Biol 16 1813 1823

32. InbalALevanonDSalzbergA 2003 Multiple roles for u-turn/ventral veinless in the development of Drosophila PNS. Development 130 2467 2478

33. ConradtB 2009 Genetic control of programmed cell death during animal development. Annu Rev Genet 43 493 523

34. BaehreckeEH 2002 How death shapes life during development. Nat Rev Mol Cell Biol 3 779 787

35. IgakiT 2009 Correcting developmental errors by apoptosis: lessons from Drosophila JNK signaling. Apoptosis 14 1021 1028

36. McNeillHDownwardJ 1999 Apoptosis: Ras to the rescue in the fly eye. Curr Biol 9 R176 179

37. RichardsonHKumarS 2002 Death to flies: Drosophila as a model system to study programmed cell death. J Immunol Methods 265 21 38

38. MolchadskyARivlinNBroshRRotterVSarigR 2010 p53 is balancing development, differentiation and de-differentiation to assure cancer prevention. Carcinogenesis 31 1501 1508

39. SchmeichelKL 2004 A fly's eye view of tumor progression and metastasis. Breast Cancer Res 6 82 83

40. BalzerEMKonstantopoulosK 2011 Intercellular adhesion: mechanisms for growth and metastasis of epithelial cancers. Wiley Interdiscip Rev Syst Biol Med

41. WirtzDKonstantopoulosKSearsonPC 2011 The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nat Rev Cancer 11 512 522

42. MichlPDownwardJ 2006 CUTL1: a key mediator of TGFbeta-induced tumor invasion. Cell Cycle 5 132 134

43. HaradaRBerubeGTamplinOJDenis-LaroseCNepveuA 1995 DNA-binding specificity of the cut repeats from the human Cut-like protein. Mol Cell Biol 15 129 140

44. IulianellaASharmaMVanden HeuvelGBTrainorPA 2009 Cux2 functions downstream of Notch signaling to regulate dorsal interneuron formation in the spinal cord. Development 136 2329 2334

45. SharmaMFopmaABrantleyJGVanden HeuvelGB 2004 Coexpression of Cux-1 and Notch signaling pathway components during kidney development. Dev Dyn 231 828 838

46. VerhagenAMVauxDL 2002 Cell death regulation by the mammalian IAP antagonist Diablo/Smac. Apoptosis 7 163 166

47. ChipukJEGreenDR 2009 PUMA cooperates with direct activator proteins to promote mitochondrial outer membrane permeabilization and apoptosis. Cell Cycle 8 2692 2696

48. WassermanWWSandelinA 2004 Applied bioinformatics for the identification of regulatory elements. Nat Rev Genet 5 276 287

49. NoyesMBChristensenRGWakabayashiAStormoGDBrodskyMH 2008 Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites. Cell 133 1277 1289

50. SiepelABejeranoGPedersenJSHinrichsASHouM 2005 Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res 15 1034 1050

51. LovegroveBSomoesSRivasMLSotillosSJohnsonK 2006 Co-ordinated control of cell adhesion, cell polarity and cytoskeleton underlies Hox induced organogenesis in Drosophila. Curr Biol 16 2206 2216

52. PiHWuHJChienCT 2001 A dual function of phyllopod in Drosophila external sensory organ development: cell fate specification of sensory organ precursor and its progeny. Development 128 2699 2710

53. GrueberWBJanLYJanYN 2003 Different levels of the homeodomain protein Cut regulate distinct dendrite branching patterns of Drosophila multidendritic neurons. Cell 112 805 818

54. HueberSDBezdanDHenzSRBlankMWuH 2007 Comparative analysis of Hox downstream genes in Drosophila. Development 134 381 392

55. LohmannIMcGinnisNBodmerMMcGinnisW 2002 The Drosophila Hox gene Deformed sculpts head morphology via direct regulation of the apoptosis activator reaper. Cell 110 457 466

56. StobePSteinSMHabring-MullerABezdanDFuchsAL 2009 Multifactorial regulation of a Hox target gene. PLoS Genet 5 e1000412 doi:10.1371/journal.pgen.1000412

57. ZhaiZSteinMALohmannI 2009 Expression of the apoptosis gene reaper in homeotic, segmentation and other mutants in Drosophila. Gene Expr Patterns 9 357 363

58. BaroloSCarverLAPosakonyJW 2000 GFP and β-galactosidase transformation vectors for promoter/enhancer analysis in Drosophila. Biotechniques 29 726 732

59. BoyALZhaiZHabring-MullerAKussler-SchneiderYKasparP 2010 Vectors for efficient and high-throughput construction of fluorescent Drosophila reporters using the PhiC31 site-specific integration system. Genesis 48 452 456

60. KosmanDMizutaniCMLemonsDCoxWGMcGinnisW 2004 Multiplex detection of RNA expression in Drosophila embryos. Science 305 846

61. ZhaiZFuchsALLohmannI 2010 Cellular analysis of newly identified Hox downstream genes in Drosophila. Eur J Cell Biol 89 273 278

62. StratigopoulosGLeDucCACremonaMLChungWKLeibelRL 2011 Cut-like homeobox 1 (CUX1) regulates expression of the fat mass and obesity-associated and retinitis pigmentosa GTPase regulator-interacting protein-1-like (RPGRIP1L) genes and coordinates leptin receptor signaling. J Biol Chem 286 2155 2170

63. BlochlingerKJanLYJanYN 1993 Postembryonic patterns of expression of cut, a locus regulating sensory organ identity in Drosophila. Development 117 441 450

64. JackJDeLottoY 1995 Structure and regulation of a complex locus: the cut gene of Drosophila. Genetics 139 1689 1700

65. KruppJJYaichLEWessellsRJBodmerR 2005 Identification of genetic loci that interact with cut during Drosophila wing-margin development. Genetics 170 1775 1795

66. MicchelliCARulifsonEJBlairSS 1997 The function and regulation of cut expression on the wing margin of Drosophila: Notch, Wingless and a dominant negative role for Delta and Serrate. Development 124 1485 1495

67. LudlowCChoyRBlochlingerK 1996 Functional analysis of Drosophila and mammalian Cut proteins in flies. Dev Biol 178 149 159