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. 1999 Feb 15;18(4):916–925. doi: 10.1093/emboj/18.4.916

The role of RBF in the introduction of G1 regulation during Drosophila embryogenesis.

W Du 1, N Dyson 1
PMCID: PMC1171184  PMID: 10022834

Abstract

The first appearance of G1 during Drosophila embryogenesis, at cell cycle 17, is accompanied by the down-regulation of E2F-dependent transcription. Mutant alleles of rbf were generated and analyzed to determine the role of RBF in this process. Embryos lacking both maternal and zygotic RBF products show constitutive expression of PCNA and RNR2, two E2F-regulated genes, indicating that RBF is required for their transcriptional repression. Despite the ubiquitous expression of E2F target genes, most epidermal cells enter G1 normally. Rather than pausing in G1 until the appropriate time for cell cycle progression, many of these cells enter an ectopic S-phase. These results indicate that the repression of E2F target genes by RBF is necessary for the maintenance but not the initiation of a G1 phase. The phenotype of RBF-deficient embryos suggests that rbf has a function that is complementary to the roles of dacapo and fizzy-related in the introduction of G1 during Drosophila embryogenesis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Asano M., Nevins J. R., Wharton R. P. Ectopic E2F expression induces S phase and apoptosis in Drosophila imaginal discs. Genes Dev. 1996 Jun 1;10(11):1422–1432. doi: 10.1101/gad.10.11.1422. [DOI] [PubMed] [Google Scholar]
  2. Clarke A. R., Maandag E. R., van Roon M., van der Lugt N. M., van der Valk M., Hooper M. L., Berns A., te Riele H. Requirement for a functional Rb-1 gene in murine development. Nature. 1992 Sep 24;359(6393):328–330. doi: 10.1038/359328a0. [DOI] [PubMed] [Google Scholar]
  3. Cobrinik D., Lee M. H., Hannon G., Mulligan G., Bronson R. T., Dyson N., Harlow E., Beach D., Weinberg R. A., Jacks T. Shared role of the pRB-related p130 and p107 proteins in limb development. Genes Dev. 1996 Jul 1;10(13):1633–1644. doi: 10.1101/gad.10.13.1633. [DOI] [PubMed] [Google Scholar]
  4. Dalby B., Pereira A. J., Goldstein L. S. An inverse PCR screen for the detection of P element insertions in cloned genomic intervals in Drosophila melanogaster. Genetics. 1995 Feb;139(2):757–766. doi: 10.1093/genetics/139.2.757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dawson I. A., Roth S., Artavanis-Tsakonas S. The Drosophila cell cycle gene fizzy is required for normal degradation of cyclins A and B during mitosis and has homology to the CDC20 gene of Saccharomyces cerevisiae. J Cell Biol. 1995 May;129(3):725–737. doi: 10.1083/jcb.129.3.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Du W., Vidal M., Xie J. E., Dyson N. RBF, a novel RB-related gene that regulates E2F activity and interacts with cyclin E in Drosophila. Genes Dev. 1996 May 15;10(10):1206–1218. doi: 10.1101/gad.10.10.1206. [DOI] [PubMed] [Google Scholar]
  7. Du W., Xie J. E., Dyson N. Ectopic expression of dE2F and dDP induces cell proliferation and death in the Drosophila eye. EMBO J. 1996 Jul 15;15(14):3684–3692. [PMC free article] [PubMed] [Google Scholar]
  8. Duronio R. J., Bonnette P. C., O'Farrell P. H. Mutations of the Drosophila dDP, dE2F, and cyclin E genes reveal distinct roles for the E2F-DP transcription factor and cyclin E during the G1-S transition. Mol Cell Biol. 1998 Jan;18(1):141–151. doi: 10.1128/mcb.18.1.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Duronio R. J., Brook A., Dyson N., O'Farrell P. H. E2F-induced S phase requires cyclin E. Genes Dev. 1996 Oct 1;10(19):2505–2513. doi: 10.1101/gad.10.19.2505. [DOI] [PubMed] [Google Scholar]
  10. Duronio R. J., O'Farrell P. H. Developmental control of a G1-S transcriptional program in Drosophila. Development. 1994 Jun;120(6):1503–1515. doi: 10.1242/dev.120.6.1503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Duronio R. J., O'Farrell P. H. Developmental control of the G1 to S transition in Drosophila: cyclin Eis a limiting downstream target of E2F. Genes Dev. 1995 Jun 15;9(12):1456–1468. doi: 10.1101/gad.9.12.1456. [DOI] [PubMed] [Google Scholar]
  12. Duronio R. J., O'Farrell P. H., Xie J. E., Brook A., Dyson N. The transcription factor E2F is required for S phase during Drosophila embryogenesis. Genes Dev. 1995 Jun 15;9(12):1445–1455. doi: 10.1101/gad.9.12.1445. [DOI] [PubMed] [Google Scholar]
  13. Dyson N. The regulation of E2F by pRB-family proteins. Genes Dev. 1998 Aug 1;12(15):2245–2262. doi: 10.1101/gad.12.15.2245. [DOI] [PubMed] [Google Scholar]
  14. Edgar B. A., Datar S. A. Zygotic degradation of two maternal Cdc25 mRNAs terminates Drosophila's early cell cycle program. Genes Dev. 1996 Aug 1;10(15):1966–1977. doi: 10.1101/gad.10.15.1966. [DOI] [PubMed] [Google Scholar]
  15. Edgar B. A., O'Farrell P. H. Genetic control of cell division patterns in the Drosophila embryo. Cell. 1989 Apr 7;57(1):177–187. doi: 10.1016/0092-8674(89)90183-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Edgar B. A., O'Farrell P. H. The three postblastoderm cell cycles of Drosophila embryogenesis are regulated in G2 by string. Cell. 1990 Aug 10;62(3):469–480. doi: 10.1016/0092-8674(90)90012-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Foe V. E., Alberts B. M. Studies of nuclear and cytoplasmic behaviour during the five mitotic cycles that precede gastrulation in Drosophila embryogenesis. J Cell Sci. 1983 May;61:31–70. doi: 10.1242/jcs.61.1.31. [DOI] [PubMed] [Google Scholar]
  18. Foe V. E. Mitotic domains reveal early commitment of cells in Drosophila embryos. Development. 1989 Sep;107(1):1–22. [PubMed] [Google Scholar]
  19. Follette P. J., Duronio R. J., O'Farrell P. H. Fluctuations in cyclin E levels are required for multiple rounds of endocycle S phase in Drosophila. Curr Biol. 1998 Feb 12;8(4):235–238. doi: 10.1016/s0960-9822(98)70089-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hao X. F., Alphey L., Bandara L. R., Lam E. W., Glover D., La Thangue N. B. Functional conservation of the cell cycle-regulating transcription factor DRTF1/E2F and its pathway of control in Drosophila melanogaster. J Cell Sci. 1995 Sep;108(Pt 9):2945–2954. doi: 10.1242/jcs.108.9.2945. [DOI] [PubMed] [Google Scholar]
  21. Jacks T., Fazeli A., Schmitt E. M., Bronson R. T., Goodell M. A., Weinberg R. A. Effects of an Rb mutation in the mouse. Nature. 1992 Sep 24;359(6393):295–300. doi: 10.1038/359295a0. [DOI] [PubMed] [Google Scholar]
  22. Knoblich J. A., Sauer K., Jones L., Richardson H., Saint R., Lehner C. F. Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation. Cell. 1994 Apr 8;77(1):107–120. doi: 10.1016/0092-8674(94)90239-9. [DOI] [PubMed] [Google Scholar]
  23. Kowalik T. F., DeGregori J., Schwarz J. K., Nevins J. R. E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis. J Virol. 1995 Apr;69(4):2491–2500. doi: 10.1128/jvi.69.4.2491-2500.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Krek W., Xu G., Livingston D. M. Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint. Cell. 1995 Dec 29;83(7):1149–1158. doi: 10.1016/0092-8674(95)90141-8. [DOI] [PubMed] [Google Scholar]
  25. Lane M. E., Sauer K., Wallace K., Jan Y. N., Lehner C. F., Vaessin H. Dacapo, a cyclin-dependent kinase inhibitor, stops cell proliferation during Drosophila development. Cell. 1996 Dec 27;87(7):1225–1235. doi: 10.1016/s0092-8674(00)81818-8. [DOI] [PubMed] [Google Scholar]
  26. Lee E. Y., Chang C. Y., Hu N., Wang Y. C., Lai C. C., Herrup K., Lee W. H., Bradley A. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature. 1992 Sep 24;359(6393):288–294. doi: 10.1038/359288a0. [DOI] [PubMed] [Google Scholar]
  27. Lee E. Y., Hu N., Yuan S. S., Cox L. A., Bradley A., Lee W. H., Herrup K. Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation. Genes Dev. 1994 Sep 1;8(17):2008–2021. doi: 10.1101/gad.8.17.2008. [DOI] [PubMed] [Google Scholar]
  28. Lee M. H., Williams B. O., Mulligan G., Mukai S., Bronson R. T., Dyson N., Harlow E., Jacks T. Targeted disruption of p107: functional overlap between p107 and Rb. Genes Dev. 1996 Jul 1;10(13):1621–1632. doi: 10.1101/gad.10.13.1621. [DOI] [PubMed] [Google Scholar]
  29. Lehner C. F., O'Farrell P. H. Expression and function of Drosophila cyclin A during embryonic cell cycle progression. Cell. 1989 Mar 24;56(6):957–968. doi: 10.1016/0092-8674(89)90629-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lehner C. F., O'Farrell P. H. The roles of Drosophila cyclins A and B in mitotic control. Cell. 1990 May 4;61(3):535–547. doi: 10.1016/0092-8674(90)90535-m. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. MacAuley A., Cross J. C., Werb Z. Reprogramming the cell cycle for endoreduplication in rodent trophoblast cells. Mol Biol Cell. 1998 Apr;9(4):795–807. doi: 10.1091/mbc.9.4.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mulligan G., Jacks T. The retinoblastoma gene family: cousins with overlapping interests. Trends Genet. 1998 Jun;14(6):223–229. doi: 10.1016/s0168-9525(98)01470-x. [DOI] [PubMed] [Google Scholar]
  33. Qin X. Q., Livingston D. M., Kaelin W. G., Jr, Adams P. D. Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10918–10922. doi: 10.1073/pnas.91.23.10918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Richardson H. E., O'Keefe L. V., Reed S. I., Saint R. A Drosophila G1-specific cyclin E homolog exhibits different modes of expression during embryogenesis. Development. 1993 Nov;119(3):673–690. doi: 10.1242/dev.119.3.673. [DOI] [PubMed] [Google Scholar]
  35. Richardson H., O'Keefe L. V., Marty T., Saint R. Ectopic cyclin E expression induces premature entry into S phase and disrupts pattern formation in the Drosophila eye imaginal disc. Development. 1995 Oct;121(10):3371–3379. doi: 10.1242/dev.121.10.3371. [DOI] [PubMed] [Google Scholar]
  36. Royzman I., Whittaker A. J., Orr-Weaver T. L. Mutations in Drosophila DP and E2F distinguish G1-S progression from an associated transcriptional program. Genes Dev. 1997 Aug 1;11(15):1999–2011. doi: 10.1101/gad.11.15.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Shan B., Lee W. H. Deregulated expression of E2F-1 induces S-phase entry and leads to apoptosis. Mol Cell Biol. 1994 Dec;14(12):8166–8173. doi: 10.1128/mcb.14.12.8166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sigrist S. J., Lehner C. F. Drosophila fizzy-related down-regulates mitotic cyclins and is required for cell proliferation arrest and entry into endocycles. Cell. 1997 Aug 22;90(4):671–681. doi: 10.1016/s0092-8674(00)80528-0. [DOI] [PubMed] [Google Scholar]
  39. Sigrist S., Jacobs H., Stratmann R., Lehner C. F. Exit from mitosis is regulated by Drosophila fizzy and the sequential destruction of cyclins A, B and B3. EMBO J. 1995 Oct 2;14(19):4827–4838. doi: 10.1002/j.1460-2075.1995.tb00164.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Smith A. V., Orr-Weaver T. L. The regulation of the cell cycle during Drosophila embryogenesis: the transition to polyteny. Development. 1991 Aug;112(4):997–1008. doi: 10.1242/dev.112.4.997. [DOI] [PubMed] [Google Scholar]
  41. Soto M. C., Chou T. B., Bender W. Comparison of germline mosaics of genes in the Polycomb group of Drosophila melanogaster. Genetics. 1995 May;140(1):231–243. doi: 10.1093/genetics/140.1.231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Spradling A., Orr-Weaver T. Regulation of DNA replication during Drosophila development. Annu Rev Genet. 1987;21:373–403. doi: 10.1146/annurev.ge.21.120187.002105. [DOI] [PubMed] [Google Scholar]
  43. Weiss A., Herzig A., Jacobs H., Lehner C. F. Continuous Cyclin E expression inhibits progression through endoreduplication cycles in Drosophila. Curr Biol. 1998 Feb 12;8(4):239–242. doi: 10.1016/s0960-9822(98)70090-9. [DOI] [PubMed] [Google Scholar]
  44. Wu X., Levine A. J. p53 and E2F-1 cooperate to mediate apoptosis. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3602–3606. doi: 10.1073/pnas.91.9.3602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. de Nooij J. C., Hariharan I. K. Uncoupling cell fate determination from patterned cell division in the Drosophila eye. Science. 1995 Nov 10;270(5238):983–985. doi: 10.1126/science.270.5238.983. [DOI] [PubMed] [Google Scholar]
  46. de Nooij J. C., Letendre M. A., Hariharan I. K. A cyclin-dependent kinase inhibitor, Dacapo, is necessary for timely exit from the cell cycle during Drosophila embryogenesis. Cell. 1996 Dec 27;87(7):1237–1247. doi: 10.1016/s0092-8674(00)81819-x. [DOI] [PubMed] [Google Scholar]

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