The bHLH Factors Extramacrochaetae and Daughterless Control Cell Cycle in Imaginal Discs through the Transcriptional Regulation of the Phosphatase
Precise control of cell proliferation is critical for normal development and tissue homeostasis. Members of the inhibitor of differentiation (Id) family of helix-loop-helix (HLH) proteins are key regulators that coordinate the balance between cell division and differentiation. These proteins exert this function in part by combining with ubiquitously expressed bHLH transcription factors (E proteins), preventing these transcription factors from forming functional hetero- or homodimeric DNA binding complexes. Deregulation of the activity of Id proteins frequently leads to tumour formation. The Daughterless (Da) and Extramacrochaetae (Emc) proteins are the only members of the E and Id families in Drosophila, yet their role in the control of cell proliferation has not been determined. In this study, we show that the elimination of emc or the ectopic expression of da arrests cells in the G2 phase of the cell cycle. Moreover, we demonstrate that emc controls cell proliferation via Da, which acts as a transcriptional repressor of the Cdc25 phosphatase string. These results provide an important insight into the mechanisms through which Id and E protein interactions control cell cycle progression and therefore how the disruption of the function of Id proteins can induce oncogenic transformation.
Vyšlo v časopise:
The bHLH Factors Extramacrochaetae and Daughterless Control Cell Cycle in Imaginal Discs through the Transcriptional Regulation of the Phosphatase. PLoS Genet 10(3): e32767. doi:10.1371/journal.pgen.1004233
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1004233
Souhrn
Precise control of cell proliferation is critical for normal development and tissue homeostasis. Members of the inhibitor of differentiation (Id) family of helix-loop-helix (HLH) proteins are key regulators that coordinate the balance between cell division and differentiation. These proteins exert this function in part by combining with ubiquitously expressed bHLH transcription factors (E proteins), preventing these transcription factors from forming functional hetero- or homodimeric DNA binding complexes. Deregulation of the activity of Id proteins frequently leads to tumour formation. The Daughterless (Da) and Extramacrochaetae (Emc) proteins are the only members of the E and Id families in Drosophila, yet their role in the control of cell proliferation has not been determined. In this study, we show that the elimination of emc or the ectopic expression of da arrests cells in the G2 phase of the cell cycle. Moreover, we demonstrate that emc controls cell proliferation via Da, which acts as a transcriptional repressor of the Cdc25 phosphatase string. These results provide an important insight into the mechanisms through which Id and E protein interactions control cell cycle progression and therefore how the disruption of the function of Id proteins can induce oncogenic transformation.
Zdroje
1. EdgarBA, LehnerCF (1996) Developmental control of cell cycle regulators: a fly's perspective. Science 274: 1646–1652.
2. ThompsonBJ (2010) Developmental control of cell growth and division in Drosophila. Curr Opin Cell Biol 22: 788–794.
3. AtchleyWR, FitchWM (1997) A natural classification of the basic helix-loop-helix class of transcription factors. Proc Natl Acad Sci U S A 94: 5172–5176.
4. MassariME, MurreC (2000) Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol 20: 429–440.
5. EllenbergerT, FassD, ArnaudM, HarrisonSC (1994) Crystal structure of transcription factor E47: E-box recognition by a basic region helix-loop-helix dimer. Genes Dev 8: 970–980.
6. MaPC, RouldMA, WeintraubH, PaboCO (1994) Crystal structure of MyoD bHLH domain-DNA complex: perspectives on DNA recognition and implications for transcriptional activation. Cell 77: 451–459.
7. HenthornP, McCarrick-WalmsleyR, KadeschT (1990) Sequence of the cDNA encoding ITF-1, a positive-acting transcription factor. Nucleic Acids Res 18: 677.
8. AronheimA, ShiranR, RosenA, WalkerMD (1993) The E2A gene product contains two separable and functionally distinct transcription activation domains. Proc Natl Acad Sci U S A 90: 8063–8067.
9. AronheimA, ShiranR, RosenA, WalkerMD (1993) Cell-specific expression of helix-loop-helix transcription factors encoded by the E2A gene. Nucleic Acids Res 21: 1601–1606.
10. LassarAB, DavisRL, WrightWE, KadeschT, MurreC, et al. (1991) Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo. Cell 66: 305–315.
11. BenezraR, DavisRL, LockshonD, TurnerDL, WeintraubH (1990) The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell 61: 49–59.
12. RiechmannV, van CruchtenI, SablitzkyF (1994) The expression pattern of Id4, a novel dominant negative helix-loop-helix protein, is distinct from Id1, Id2 and Id3. Nucleic Acids Res 22: 749–755.
13. SunXH, CopelandNG, JenkinsNA, BaltimoreD (1991) Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins. Mol Cell Biol 11: 5603–5611.
14. PerkJ, IavaroneA, BenezraR (2005) Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer 5: 603–614.
15. LingMT, WangX, ZhangX, WongYC (2006) The multiple roles of Id-1 in cancer progression. Differentiation 74: 481–487.
16. EngelI, MurreC (2004) E2A proteins enforce a proliferation checkpoint in developing thymocytes. Embo J 23: 202–211.
17. PeveraliFA, RamqvistT, SaffrichR, PepperkokR, BaroneMV, et al. (1994) Regulation of G1 progression by E2A and Id helix-loop-helix proteins. Embo J 13: 4291–4301.
18. SongS, CoopermanJ, LettingDL, BlobelGA, ChoiJK (2004) Identification of cyclin D3 as a direct target of E2A using DamID. Mol Cell Biol 24: 8790–8802.
19. RothschildG, ZhaoX, IavaroneA, LasorellaA (2006) E Proteins and Id2 converge on p57Kip2 to regulate cell cycle in neural cells. Mol Cell Biol 26: 4351–4361.
20. LydenD, YoungAZ, ZagzagD, YanW, GeraldW, et al. (1999) Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 401: 670–677.
21. YokotaY, MansouriA, MoriS, SugawaraS, AdachiS, et al. (1999) Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397: 702–706.
22. BotasJ, Moscoso del PradoJ, García-BellidoA (1982) Gene-dose titration analysis in the search of trans-regulatory genes in Drosophila. EMBO J 1: 307–310.
23. EllisHM, SpannDR, PosakonyJW (1990) extramacrochaetae, a negative regulator of sensory organ development in Drosophila, defines a new class of helix-loop-helix proteins. Cell 61: 27–38.
24. GarrellJ, ModolellJ (1990) The Drosophila extramacrochaetae locus, an antagonist of proneural genes that, like these genes, encodes a helix-loop-helix protein. Cell 61: 39–48.
25. CampuzanoS (2001) Emc, a negative HLH regulator with multiple functions in Drosophila development. Oncogene 20: 8299–8307.
26. BrownNL, SattlerCA, PaddockSW, CarrollSB (1995) Hairy and Emc negatively regulate morphogenetic forrow progression in the Drosophila eye. Cell 80: 879–887.
27. BaonzaA, FreemanM (2001) Notch signalling and the initiation of neural development in the Drosophila eye. Development 128: 3889–3898.
28. de CelisJF, BaonzaA, Garcia-BellidoA (1995) Behavior of extramacrochaetae mutant cells in the morphogenesis of the Drosophila wing. Mech Dev 53: 209–221.
29. BaonzaA, Garcia-BellidoA (1999) Dual role of extramacrochaetae in cell proliferation and cell differentiation during wing morphogenesis in Drosophila. Mech Dev 80: 133–146.
30. BhattacharyaA, BakerNE (2011) A network of broadly expressed HLH genes regulates tissue-specific cell fates. Cell 147: 881–892.
31. IavaroneA, GargP, LasorellaA, HsuJ, IsraelMA (1994) The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Genes Dev 8: 1270–1284.
32. LasorellaA, IavaroneA, IsraelMA (1996) Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins. Mol Cell Biol 16: 2570–2578.
33. PopovaMK, HeW, KorenjakM, DysonNJ, MoonNS (2011) Rb deficiency during Drosophila eye development deregulates EMC, causing defects in the development of photoreceptors and cone cells. J Cell Sci 124: 4203–4212.
34. LeeT, LuoL (1999) Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22: 451–461.
35. Garcia-AlonsoL, Garcia-BellidoA (1988) extramacrochaetae, a trans-acting gene of the achaete-scute complex of Drosophila is involved in cell communication. Roux's Arch. Dev. Biol 197: 328–338.
36. WhiteK, GretherME, AbramsJM, YoungL, FarrellK, et al. (1994) Genetic control of programmed cell death in Drosophila. Science 264: 677–682.
37. NeufeldTP, de la CruzAF, JohnstonLA, EdgarBA (1998) Coordination of growth and cell division in the Drosophila wing. Cell 93: 1183–1193.
38. LehmanDA, PattersonB, JohnstonLA, BalzerT, BrittonJS, et al. (1999) Cis-regulatory elements of the mitotic regulator, string/Cdc25. Development 126: 1793–1803.
39. NègreN, BrownCD, MaL, BristowCA, MillerSW, et al. (2011) Nature 471: 527–31.
40. WongMC, CastanonI, BayliesMK (2008) Daughterless dictates Twist activity in a context-dependent manner during somatic myogenesis. Dev Biol 317: 417–429.
41. O'BrochtaD, BryantPJ (1985) A zone of non-proliferating cells at a lineage restriction boundary in Drosophila. Nature 313: 138–141.
42. PhillipsRG, WhittleJRS (1993) wingless expression mediates determination of peripheral nervous system elements in late stages of Drosophila wing disc development. Development 118: 427–438.
43. JohnstonLA, EdgarBA (1998) Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing. Nature 394: 82–84.
44. DelidakisC, Artavanis-TsakonasS (1992) The Enhancer of split locus of Drosophila encodes seven independent helix-loop-helix proteins. Proc Nat Acad Sci USA 89: 8731–8735.
45. KnustE, SchronsH, GraweF, Campos-OrtegaJA (1992) Seven genes of the Enhancer of split complex of Drosophila melanogaster encode Helix-loop-Helix protein. Genetics 132: 505–518.
46. JenningsB, PreissA, DelidakisC, BrayS (1994) The Nocth signalling pathway is requiered for Enhancer of split bHLH protein expression during neurogenesis in the Drosophila embryo. Development 120: 3537–3548.
47. de CelisJF, de CelisJ, LigoxiarsP, PreissA, DelidakisC, et al. (1996) Functional relationships between Notch and bHLH genes of the E(spl) complex: the E(spl) genes mediate only a subset of Notch activies during imaginal development. Development 122: 2719–2728.
48. San JuanBP, Andrade-ZapataI, BaonzaA (2012) The bHLH factors Dpn and members of the E(spl) complex mediate the function of Notch signalling regulating cell proliferation during wing disc development. Biol Open 1: 667–676.
49. HaraE, YamaguchiT, NojimaH, IdeT, CampisiJ, et al. (1994) Id-related genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts. J Biol Chem 269: 2139–2145.
50. LasorellaA, BoldriniR, DominiciC, DonfrancescoA, YokotaY, et al. (2002) Id2 is critical for cellular proliferation and is the oncogenic effector of N-myc in human neuroblastoma. Cancer Res 62: 301–306.
51. VaessinH, BrandM, JanLY, JanYN (1994) daughterless is essential for neuronal precursor differentiation but not for initiation of neuronal precursor formation in Drosophila embryo. Development 120: 935–945.
52. BrownNL, SattlerCA, PaddockSW, CarrollSB (1995) Hairy and emc negatively regulate morphogenetic furrow progression in the Drosophila eye. Cell 80: 879–887.
53. ReisT, EdgarBA (2004) Negative regulation of dE2F1 by cyclin-dependent kinases controls cell cycle timing. Cell 117: 253–264.
54. BaonzaA, MurawskyCM, TraversAA, FreemanM (2002) Pointed and Tramtrack69 establish an EGFR-dependent transcriptional switch to regulate mitosis. Nat Cell Biol 4: 976–980.
55. BhattacharyaA, BakerNE (2009) The HLH protein Extramacrochaetae is required for R7 cell and cone cell fates in the Drosophila eye. Dev Biol 327: 288–300.
56. KylstenP, SaintR (1997) Imaginal tissues of Drosophila melanogaster exhibit different modes of cell proliferation control. Dev Biol 192: 509–522.
57. LasorellaA, UoT, IavaroneA (2001) Id proteins at the cross-road of development and cancer. Oncogene 20: 8326–8333.
58. ItoK, AwanoW, SuzukiK, HiromiY, YamamotoD (1997) The Drosophila mushroom body is a quadruple structure of clonal units each of which contains a virtually identical set of neurones and glial cells. Development 124: 761–771.
59. SandmannT, JakobsenJS, FurlongEM (2007) ChIP-on-chip protocol for genome-wide analysis of transcription factor binding in Drosophila melanogaster embryos. Nature protocols 1: 2839–2855.
60. MurreC, McCawPS, VäsinH, CaudyM, JanLY, et al. (1989) Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell 58: 537–544.
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2014 Číslo 3
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Worldwide Patterns of Ancestry, Divergence, and Admixture in Domesticated Cattle
- Genome-Wide DNA Methylation Analysis of Human Pancreatic Islets from Type 2 Diabetic and Non-Diabetic Donors Identifies Candidate Genes That Influence Insulin Secretion
- Genetic Dissection of Photoreceptor Subtype Specification by the Zinc Finger Proteins Elbow and No ocelli
- GC-Rich DNA Elements Enable Replication Origin Activity in the Methylotrophic Yeast