The Homeodomain Iroquois Proteins Control Cell Cycle Progression and Regulate the Size of Developmental Fields

English version České info

The correct development of body organs, with their characteristic size and shape, requires the coordination of cell division and cell differentiation. Here we show that the Iroquois proteins (Irx in vertebrates) slow down cell division in the Drosophila imaginal discs, in addition to their well-known role in cell fate and territorial specification. In humans, inactivating mutations at the Irx genes are associated to several types of cancer, thus allowing their classification as tumour suppressor genes. We have observed that Drosophila Iroquois genes similarly behave as tumour suppressor genes. Iroquois proteins belong to a family of homeodomain-containing transcriptional regulators. However, our results indicate that they control cell division by a transcription independent mechanism based on their physical interaction with Cyclin E containing complexes, a key player in cell-cycle progression. We have identified two evolutionary conserved domains of Iroquois proteins, different from the homeodomain, involved in that interaction. This new function of Iroquois proteins places them in a key position to coordinate growth and differentiation during normal development. Our results further suggest a molecular mechanism for their role in tumour suppression. Future studies of Irx genes should help to determine if a similar mechanism could operate to help cancer progression when Irx activity is compromised.

Vyšlo v časopise: The Homeodomain Iroquois Proteins Control Cell Cycle Progression and Regulate the Size of Developmental Fields. PLoS Genet 11(8): e32767. doi:10.1371/journal.pgen.1005463
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005463

Souhrn

Zdroje

1. Schwank G, Basler K (2010) Regulation of organ growth by morphogen gradients. Cold Spring Harb Perspect Biol. 2: a001669. doi: 10.1101/cshperspect.a001669 20182606

2. Amore G, Casares F (2010) Size matters: the contribution of cell proliferation to the progression of the specification Drosophila eye gene regulatory network. Dev Biol 344: 569–577. doi: 10.1016/j.ydbio.2010.06.015 20599903

3. Dekanty A, Milan M (2011) The interplay between morphogens and tissue growth. EMBO Rep 12: 1003–1010. doi: 10.1038/embor.2011.172 21886183

4. Towers M, Tickle C (2009) Growing models of vertebrate limb development. Development 136: 179–190. doi: 10.1242/dev.024158 19103802

5. Cooper KL, Hu JK, ten Berge D, Fernandez-Teran M, Ros MA, Tabin CJ (2011) Initiation of proximal-distal patterning in the vertebrate limb by signals and growth. Science 332: 1083–1086. doi: 10.1126/science.1199499 21617075

6. Rosello-Diez A, Ros MA, Torres M (2011) Diffusible signals, not autonomous mechanisms, determine the main proximodistal limb subdivision. Science 332: 1086–1088. doi: 10.1126/science.1199489 21617076

7. Kenyon KL, Ranade SS, Curtiss J, Mlodzik M, Pignoni F (2003) Coordinating proliferation and tissue specification to promote regional identity in the Drosophila head. Dev Cell 5: 403–414. 12967560

8. Rafel N, Milan M (2008) Notch signalling coordinates tissue growth and wing fate specification in Drosophila. Development 135: 3995–4001. doi: 10.1242/dev.027789 18987026

9. Gomez-Skarmeta JL, Diez del Corral R, de la Calle-Mustienes E, Ferres-Marco D, Modolell J (1996) Araucan and caupolican, two members of the novel iroquois complex, encode homeoproteins that control proneural and vein-forming genes. Cell 85: 95–105. 8620542

10. McNeill H, Yang CH, Brodsky M, Ungos J, Simon MA (1997) mirror encodes a novel PBX-class homeoprotein that functions in the definition of the dorsal-ventral border in the Drosophila eye. Genes Dev 11: 1073–1082. 9136934

11. Burglin TR (1997) Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. Nucleic Acids Res 25: 4173–4180. 9336443

12. Cavodeassi F, Modolell J, Gomez-Skarmeta JL (2001) The Iroquois family of genes: from body building to neural patterning. Development 128: 2847–2855. 11532909

13. Cavodeassi F, Modolell J, Campuzano S (2000) The Iroquois homeobox genes function as dorsal selectors in the Drosophila head. Development 127: 1921–1929. 10751180

14. Cavodeassi F, Diez Del Corral R, Campuzano S, Dominguez M (1999) Compartments and organising boundaries in the Drosophila eye: the role of the homeodomain Iroquois proteins. Development 126: 4933–4942. 10529412

15. Diez del Corral R, Aroca P, Gomez-Skarmeta JL, Cavodeassi F, Modolell J (1999) The Iroquois homeodomain proteins are required to specify body wall identity in Drosophila. Genes Dev 13: 1754–1761. 10398687

16. Cho KO, Choi KW. (1998) Fringe is essential for mirror symmetry and morphogenesis in the Drosophila eye. Nature 396: 272–276. 9834034

17. Dominguez M, de Celis JF (1998) A dorsal/ventral boundary established by Notch controls growth and polarity in the Drosophila eye. Nature 396: 276–278. 9834035

18. Dominguez M, Casares F (2005) Organ specification-growth control connection: new in-sights from the Drosophila eye-antennal disc. Dev Dyn 232: 673–684. 15704149

19. Pichaud F, Casares F (2000) homothorax and iroquois-C genes are required for the establishment of territories within the developing eye disc. Mech Dev 96: 15–25. 10940621

20. Bennett KL, Karpenko M, Lin MT, Claus R, Arab K, Dyckhoff G, et al. (2008) Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma. Cancer Res 68: 4494–4499. doi: 10.1158/0008-5472.CAN-07-6509 18559491

21. Lu Y, Yu Y, Zhu Z, Xu H, Ji J, Bu L, et al. (2005) Identification of a new target region by loss of heterozygosity at 5p15.33 in sporadic gastric carcinomas: genotype and phenotype related. Cancer Lett 224: 329–337. 15914283

22. Guo X, Liu W, Pan Y, Ni P, Ji J, Guo L, et al. (2010) Homeobox gene IRX1 is a tumor suppressor gene in gastric carcinoma. Oncogene 29: 3908–3920. doi: 10.1038/onc.2010.143 20440264

23. Nguyen HH, Takata R, Akamatsu S, Shigemizu D, Tsunoda T, Furihata M, et al. (2012) IRX4 at 5p15 suppresses prostate cancer growth through the interaction with vitamin D receptor, conferring prostate cancer susceptibility. Hum Mol Genet 21: 2076–2085. doi: 10.1093/hmg/dds025 22323358

24. Wolff T, Ready DF (1993) Pattern formation in the Drosophila retina. In: Bate M, Martinez-Arias A, editors. The development of Drosophila melanogaster. Cold Spring Harbor Lab Press, Vol II p. 1277–1325.

25. Treisman JE, Rubin GM (1995) wingless inhibits morphogenetic furrow movement in the Drosophila eye disc. Development 121: 3519–3527. 8582266

26. Mazzoni EO, Celik A, Wernet MF, Vasiliauskas D, Johnston RJ, Cook TA, et al. (2008) Iroquois complex genes induce co-expression of rhodopsins in Drosophila. PLoS Biol 6:e97. doi: 10.1371/journal.pbio.0060097 18433293

27. Organista MF, De Celis JF (2013) The Spalt transcription factors regulate cell proliferation, survival and epithelial integrity downstream of the Decapentaplegic signalling pathway. Biol Open 2: 37–48. doi: 10.1242/bio.20123038 23336075

28. Neufeld TP, de la Cruz AF, Johnston LA, Edgar BA (1998) Coordination of growth and cell division in the Drosophila wing. Cell 93: 1183–1193. 9657151

29. Edgar BA, O'Farrell PH (1990) The three postblastoderm cell cycles of Drosophila embryogenesis are regulated in G2 by string. Cell 62: 469–480. 2199063

30. McGuire SE, Roman G, Davis RL (2004) Gene expression systems in Drosophila: a synthesis of time and space. Trends Genet 20: 384–391. 15262411

31. Cruz C, Glavic A, Casado M, de Celis JF (2009) A gain-of-function screen identifying genes required for growth and pattern formation of the Drosophila melanogaster wing. Genetics 183: 1005–1026. doi: 10.1534/genetics.109.107748 19737745

32. Lee LA, Orr-Weaver TL (2003) Regulation of cell cycles in Drosophila development: intrinsic and extrinsic cues. Annu Rev Genet 37: 545–578. 14616073

33. Wang SL, Hawkins CJ, Yoo SJ, Muller HA, Hay BA (1999) The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Cell 98: 453–463. 10481910

34. Chen P, Nordstrom W, Gish B, Abrams JM (1996) grim, a novel cell death gene in Drosophila. Genes Dev 10: 1773–1782. 8698237

35. Waldron JA, Jones CI, Towler BP, Pashler AL, Grima DP, Hebbes S, et al. (2015) Xrn1/Pacman affects apoptosis and regulates expression of hid and reaper. Biol Open. 4: 649–660. doi: 10.1242/bio.201410199 25836675

36. Moberg KH, Bell DW, Wahrer DC, Haber DA, Hariharan IK (2001) Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 413: 311–316. 11565033

37. Aldaz S, Morata G, Azpiazu N (2003) The Pax-homeobox gene eyegone is involved in the subdivision of the thorax of Drosophila. Development 130: 4473–4482. 12900462

38. Wang SH, Simcox A, Campbell G (2000) Dual role for Drosophila epidermal growth factor re.ceptor signaling in early wing disc development. Genes Dev 14: 2271–2276. 10995384

39. de Navascues J, Modolell J (2007) tailup, a LIM-HD gene, and Iro-C cooperate in Drosophila dorsal mesothorax specification. Development 134: 1779–1788. 17409113

40. White AE, Leslie ME, Calvi BR, Marzluff WF, Duronio RJ (2007) Developmental and cell cycle regulation of the Drosophila histone locus body. Mol Biol Cell 18: 2491–2502. 17442888

41. Clurman BE, Sheaff RJ, Thress K, Groudine M, Roberts JM (1996) Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation. Genes Dev 10:1979–1690. 8769642

42. Bilioni A, Craig G, Hill C, McNeill H (2005) Iroquois transcription factors recognize a unique motif to mediate transcriptional repression in vivo. Proc Natl Acad Sci U S A 102: 14671–14676. 16203991

43. Noyes MB, Christensen RG, Wakabayashi A, Stormo GD, Brodsky MH, Wolfe SA (2008) Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites. Cell 133: 1277–1289. doi: 10.1016/j.cell.2008.05.023 18585360

44. Ades SE, Sauer RT (1995) Specificity of minor-groove and major-groove interactions in a homeodomain-DNA complex. Biochemistry 34: 14601–14608. 7578067

45. Ferres-Marco D, Gutierrez-Garcia I, Vallejo DM, Bolivar J, Gutierrez-Avino FJ, Dominguez M (2006) Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439: 430–436. 16437107

46. Yu FX, Guan KL (2013) The Hippo pathway: regulators and regulations. Genes Dev 27: 355–371. doi: 10.1101/gad.210773.112 23431053

47. Zhao B, Tumaneng K, Guan KL (2011) The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nature Cell Biol 13: 877–883. doi: 10.1038/ncb2303 21808241

48. Del Bene F, Wittbrodt J (2005). Cell cycle control by homeobox genes in development and disease. Semin Cell Dev Biol 16: 449–460. 15840452

49. Baig J, Chanut F, Kornberg TB, Klebes A (2010) The chromatin-remodeling protein Osa interacts with CyclinE in Drosophila eye imaginal discs. Genetics 184: 731–44. doi: 10.1534/genetics.109.109967 20008573

50. Lecona E, Rojas LA, Bonasio R, Johnston A, Fernandez-Capetillo O, Reinberg D (2013) Polycomb protein SCML2 regulates the cell cycle by binding and modulating CDK/CYCLIN/p21 complexes. PLoS Biol 11: e1001737. doi: 10.1371/journal.pbio.1001737 24358021

51. Zecca M, Struhl G (2002) Control of growth and patterning of the Drosophila wing imaginal disc by EGFR-mediated signaling. Development 129: 1369–1376. 11880346

52. Heberlein U, Borod ER, Chanut FA (1998) Dorsoventral patterning in the Drosophila retina by wingless. Development 125: 567–577. 9435278

53. Lee JD, Treisman JE (2001) The role of Wingless signaling in establishing the anteroposterior and dorsoventral axes of the eye disc. Development 128: 1519–1529. 11290291

54. Maurel-Zaffran C, Treisman JE (2000) pannier acts upstream of wingless to direct dorsal eye disc development in Drosophila. Development 127: 1007–1016. 10662640

55. Myrthue A, Rademacher BL, Pittsenbarger J, Kutyba-Brooks B, Gantner M, Qian DZ, et al. (2008) The iroquois homeobox gene 5 is regulated by 1,25-dihydroxyvitamin D3 in human prostate cancer and regulates apoptosis and the cell cycle in LNCaP prostate cancer cells. Clin Cancer Res 14: 3562–3570. doi: 10.1158/1078-0432.CCR-07-4649 18519790

56. Martorell O, Barriga FM, Merlos-Suarez A, Stephan-Otto Attolini C, Casanova J, Batlle E, et al. (2014) Iro/IRX transcription factors negatively regulate Dpp/TGF-beta pathway activity during intestinal tumorigenesis. EMBO Rep 15: 1210–1218. doi: 10.15252/embr.201438622 25296644

57. Hwang HC, Clurman BE (2005) Cyclin E in normal and neoplastic cell cycles. Oncogene 24: 2776–2786. 15838514

58. Bischof J, Maeda RK, Hediger M, Karch F, Basler K (2007) An optimized transgenesis system for Drosophila using germ-line-specific phiC31 integrases. Proc Natl Acad Sci U S A 104: 3312–3317. 17360644

59. Carrasco-Rando M, Tutor AS, Prieto-Sanchez S, Gonzalez-Perez E, Barrios N, Letizia A, et al. (2011) Drosophila araucan and caupolican integrate intrinsic and signalling inputs for the acquisition by muscle progenitors of the lateral transverse fate. PLoS Genet 7: e1002186. doi: 10.1371/journal.pgen.1002186 21811416

60. Villa-Cuesta E, Gonzalez-Perez E, Modolell J (2007) Apposition of iroquois expressing and non-expressing cells leads to cell sorting and fold formation in the Drosophila imaginal wing disc. BMC Dev Biol 7: 106. 17880703