Requirements for dE2F function in proliferating cells and in post-mitotic differentiating cells. (original) (raw)

EMBO J. 1996 Jul 15; 15(14): 3676–3683.

Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.

Abstract

The transcription factor E2F is a target of the retinoblastoma tumor suppressor protein (pRB) and may mediate pRB regulation of S phase entry in mammalian cells. The recent identification of mutant alleles of the Drosophila E2F gene (dE2F) has shown that dE2F is required for embryogenesis. dE2F-mutant embryos lack a co-ordinated program of gene expression which accompanies S phase entry and DNA synthesis declines to levels that are barely detectable. We have investigated the role of the dE2F gene at later stages of development. dE2F is expressed in several larval tissues and is required for cell proliferation in the eye imaginal disc. Surprisingly, dE2F expression persists in post-mitotic cells of the eye disc of third-instar larvae. The loss of dE2F function in these cells causes a novel phenotype, characterized by loss of photoreceptors and abnormal rhabdomere cell morphology. These results show that dE2F is required at multiple stages of development and suggest that E2F may have an important function in post-mitotic cells in addition to its role during cell proliferation.

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Prime FJ. Respiratory function tests for a clinician. BTTA Rev. 1973 Mar;3(1):1–12. [PubMed] [Google Scholar]
Adnane J, Shao Z, Robbins PD. The retinoblastoma susceptibility gene product represses transcription when directly bound to the promoter. J Biol Chem. 1995 Apr 14;270(15):8837–8843. [PubMed] [Google Scholar]
Alphey L, Jimenez J, White-Cooper H, Dawson I, Nurse P, Glover DM. twine, a cdc25 homolog that functions in the male and female germline of Drosophila. Cell. 1992 Jun 12;69(6):977–988. [PubMed] [Google Scholar]
Beijersbergen RL, Kerkhoven RM, Zhu L, Carlée L, Voorhoeve PM, Bernards R. E2F-4, a new member of the E2F gene family, has oncogenic activity and associates with p107 in vivo. Genes Dev. 1994 Nov 15;8(22):2680–2690. [PubMed] [Google Scholar]
Blair SS, Brower DL, Thomas JB, Zavortink M. The role of apterous in the control of dorsoventral compartmentalization and PS integrin gene expression in the developing wing of Drosophila. Development. 1994 Jul;120(7):1805–1815. [PubMed] [Google Scholar]
Bonini NM, Leiserson WM, Benzer S. The eyes absent gene: genetic control of cell survival and differentiation in the developing Drosophila eye. Cell. 1993 Feb 12;72(3):379–395. [PubMed] [Google Scholar]
Brown NL, Sattler CA, Paddock SW, Carroll SB. Hairy and emc negatively regulate morphogenetic furrow progression in the Drosophila eye. Cell. 1995 Mar 24;80(6):879–887. [PubMed] [Google Scholar]
Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR. The E2F transcription factor is a cellular target for the RB protein. Cell. 1991 Jun 14;65(6):1053–1061. [PubMed] [Google Scholar]
Dalton S. Cell cycle regulation of the human cdc2 gene. EMBO J. 1992 May;11(5):1797–1804. [PMC free article] [PubMed] [Google Scholar]
de Nooij JC, Hariharan IK. Uncoupling cell fate determination from patterned cell division in the Drosophila eye. Science. 1995 Nov 10;270(5238):983–985. [PubMed] [Google Scholar]
Duronio RJ, O'Farrell PH, Xie JE, 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. [PubMed] [Google Scholar]
Dynlacht BD, Brook A, Dembski M, Yenush L, Dyson N. DNA-binding and trans-activation properties of Drosophila E2F and DP proteins. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6359–6363. [PMC free article] [PubMed] [Google Scholar]
Flemington EK, Speck SH, Kaelin WG., Jr E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6914–6918. [PMC free article] [PubMed] [Google Scholar]
Golic KG. Site-specific recombination between homologous chromosomes in Drosophila. Science. 1991 May 17;252(5008):958–961. [PubMed] [Google Scholar]
Golic KG, Lindquist S. The FLP recombinase of yeast catalyzes site-specific recombination in the Drosophila genome. Cell. 1989 Nov 3;59(3):499–509. [PubMed] [Google Scholar]
Goodrich DW, Wang NP, Qian YW, Lee EY, Lee WH. The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle. Cell. 1991 Oct 18;67(2):293–302. [PubMed] [Google Scholar]
Hamel PA, Gill RM, Phillips RA, Gallie BL. Regions controlling hyperphosphorylation and conformation of the retinoblastoma gene product are independent of domains required for transcriptional repression. Oncogene. 1992 Apr;7(4):693–701. [PubMed] [Google Scholar]
Hamel PA, Gill RM, Phillips RA, Gallie BL. Transcriptional repression of the E2-containing promoters EIIaE, c-myc, and RB1 by the product of the RB1 gene. Mol Cell Biol. 1992 Aug;12(8):3431–3438. [PMC free article] [PubMed] [Google Scholar]
Harrison SD, Solomon N, Rubin GM. A genetic analysis of the 63E-64A genomic region of Drosophila melanogaster: identification of mutations in a replication factor C subunit. Genetics. 1995 Apr;139(4):1701–1709. [PMC free article] [PubMed] [Google Scholar]
Heberlein U, Wolff T, Rubin GM. The TGF beta homolog dpp and the segment polarity gene hedgehog are required for propagation of a morphogenetic wave in the Drosophila retina. Cell. 1993 Dec 3;75(5):913–926. [PubMed] [Google Scholar]
Helin K, Ed H. The retinoblastoma protein as a transcriptional repressor. Trends Cell Biol. 1993 Feb;3(2):43–46. [PubMed] [Google Scholar]
Helin K, Lees JA, Vidal M, Dyson N, Harlow E, Fattaey A. A cDNA encoding a pRB-binding protein with properties of the transcription factor E2F. Cell. 1992 Jul 24;70(2):337–350. [PubMed] [Google Scholar]
Hiebert SW, Chellappan SP, Horowitz JM, Nevins JR. The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F. Genes Dev. 1992 Feb;6(2):177–185. [PubMed] [Google Scholar]
Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell. 1992 Sep 18;70(6):993–1006. [PubMed] [Google Scholar]
Hsiao KM, McMahon SL, Farnham PJ. Multiple DNA elements are required for the growth regulation of the mouse E2F1 promoter. Genes Dev. 1994 Jul 1;8(13):1526–1537. [PubMed] [Google Scholar]
Ivey-Hoyle M, Conroy R, Huber HE, Goodhart PJ, Oliff A, Heimbrook DC. Cloning and characterization of E2F-2, a novel protein with the biochemical properties of transcription factor E2F. Mol Cell Biol. 1993 Dec;13(12):7802–7812. [PMC free article] [PubMed] [Google Scholar]
Johnson DG, Schwarz JK, Cress WD, Nevins JR. Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature. 1993 Sep 23;365(6444):349–352. [PubMed] [Google Scholar]
Johnson DG, Ohtani K, Nevins JR. Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression. Genes Dev. 1994 Jul 1;8(13):1514–1525. [PubMed] [Google Scholar]
Kaelin WG, Jr, Krek W, Sellers WR, DeCaprio JA, Ajchenbaum F, Fuchs CS, Chittenden T, Li Y, Farnham PJ, Blanar MA, et al. Expression cloning of a cDNA encoding a retinoblastoma-binding protein with E2F-like properties. Cell. 1992 Jul 24;70(2):351–364. [PubMed] [Google Scholar]
Knoblich JA, Lehner CF. Synergistic action of Drosophila cyclins A and B during the G2-M transition. EMBO J. 1993 Jan;12(1):65–74. [PMC free article] [PubMed] [Google Scholar]
Kowalik TF, DeGregori J, Schwarz JK, Nevins JR. E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis. J Virol. 1995 Apr;69(4):2491–2500. [PMC free article] [PubMed] [Google Scholar]
La Thangue NB. DRTF1/E2F: an expanding family of heterodimeric transcription factors implicated in cell-cycle control. Trends Biochem Sci. 1994 Mar;19(3):108–114. [PubMed] [Google Scholar]
Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. [PubMed] [Google Scholar]
Lam EW, Watson RJ. An E2F-binding site mediates cell-cycle regulated repression of mouse B-myb transcription. EMBO J. 1993 Jul;12(7):2705–2713. [PMC free article] [PubMed] [Google Scholar]
Lee EY, Hu N, Yuan SS, Cox LA, Bradley A, Lee WH, Herrup K. Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation. Genes Dev. 1994 Sep 1;8(17):2008–2021. [PubMed] [Google Scholar]
Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K. The retinoblastoma protein binds to a family of E2F transcription factors. Mol Cell Biol. 1993 Dec;13(12):7813–7825. [PMC free article] [PubMed] [Google Scholar]
Ma C, Zhou Y, Beachy PA, Moses K. The segment polarity gene hedgehog is required for progression of the morphogenetic furrow in the developing Drosophila eye. Cell. 1993 Dec 3;75(5):927–938. [PubMed] [Google Scholar]
Neuman E, Flemington EK, Sellers WR, Kaelin WG., Jr Transcription of the E2F-1 gene is rendered cell cycle dependent by E2F DNA-binding sites within its promoter. Mol Cell Biol. 1994 Oct;14(10):6607–6615. [PMC free article] [PubMed] [Google Scholar]
Nevins JR. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science. 1992 Oct 16;258(5081):424–429. [PubMed] [Google Scholar]
Ohtani K, Nevins JR. Functional properties of a Drosophila homolog of the E2F1 gene. Mol Cell Biol. 1994 Mar;14(3):1603–1612. [PMC free article] [PubMed] [Google Scholar]
Qin XQ, Livingston DM, Kaelin WG, Jr, Adams PD. 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. [PMC free article] [PubMed] [Google Scholar]
Qin XQ, Livingston DM, Ewen M, Sellers WR, Arany Z, Kaelin WG., Jr The transcription factor E2F-1 is a downstream target of RB action. Mol Cell Biol. 1995 Feb;15(2):742–755. [PMC free article] [PubMed] [Google Scholar]
Robinow S, White K. The locus elav of Drosophila melanogaster is expressed in neurons at all developmental stages. Dev Biol. 1988 Apr;126(2):294–303. [PubMed] [Google Scholar]
Sardet C, Vidal M, Cobrinik D, Geng Y, Onufryk C, Chen A, Weinberg RA. E2F-4 and E2F-5, two members of the E2F family, are expressed in the early phases of the cell cycle. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2403–2407. [PMC free article] [PubMed] [Google Scholar]
Schneider JW, Gu W, Zhu L, Mahdavi V, Nadal-Ginard B. Reversal of terminal differentiation mediated by p107 in Rb-/- muscle cells. Science. 1994 Jun 3;264(5164):1467–1471. [PubMed] [Google Scholar]
Shan B, Lee WH. Deregulated expression of E2F-1 induces S-phase entry and leads to apoptosis. Mol Cell Biol. 1994 Dec;14(12):8166–8173. [PMC free article] [PubMed] [Google Scholar]
Shan B, Zhu X, Chen PL, Durfee T, Yang Y, Sharp D, Lee WH. Molecular cloning of cellular genes encoding retinoblastoma-associated proteins: identification of a gene with properties of the transcription factor E2F. Mol Cell Biol. 1992 Dec;12(12):5620–5631. [PMC free article] [PubMed] [Google Scholar]
Tomlinson A, Kimmel BE, Rubin GM. rough, a Drosophila homeobox gene required in photoreceptors R2 and R5 for inductive interactions in the developing eye. Cell. 1988 Dec 2;55(5):771–784. [PubMed] [Google Scholar]
Weintraub SJ, Prater CA, Dean DC. Retinoblastoma protein switches the E2F site from positive to negative element. Nature. 1992 Jul 16;358(6383):259–261. [PubMed] [Google Scholar]
Weintraub SJ, Chow KN, Luo RX, Zhang SH, He S, Dean DC. Mechanism of active transcriptional repression by the retinoblastoma protein. Nature. 1995 Jun 29;375(6534):812–815. [PubMed] [Google Scholar]
Whitfield WG, Gonzalez C, Maldonado-Codina G, Glover DM. The A- and B-type cyclins of Drosophila are accumulated and destroyed in temporally distinct events that define separable phases of the G2-M transition. EMBO J. 1990 Aug;9(8):2563–2572. [PMC free article] [PubMed] [Google Scholar]
Wu X, Levine AJ. p53 and E2F-1 cooperate to mediate apoptosis. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3602–3606. [PMC free article] [PubMed] [Google Scholar]
Xu T, Harrison SD. Mosaic analysis using FLP recombinase. Methods Cell Biol. 1994;44:655–681. [PubMed] [Google Scholar]
Xu T, Rubin GM. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development. 1993 Apr;117(4):1223–1237. [PubMed] [Google Scholar]
Zamanian M, La Thangue NB. Adenovirus E1a prevents the retinoblastoma gene product from repressing the activity of a cellular transcription factor. EMBO J. 1992 Jul;11(7):2603–2610. [PMC free article] [PubMed] [Google Scholar]
Zhu L, van den Heuvel S, Helin K, Fattaey A, Ewen M, Livingston D, Dyson N, Harlow E. Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein. Genes Dev. 1993 Jul;7(7A):1111–1125. [PubMed] [Google Scholar]
Zhu L, Zhu L, Xie E, Chang LS. Differential roles of two tandem E2F sites in repression of the human p107 promoter by retinoblastoma and p107 proteins. Mol Cell Biol. 1995 Jul;15(7):3552–3562. [PMC free article] [PubMed] [Google Scholar]

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