Abstract
A 120 bp homeotic response element that is regulated specifically by Deformed in Drosophila embryos contains a single binding site for Deformed protein. However, a 24 bp sub-element containing this site does not constitute a Deformed response element. Specific activation requires a second region in the 120 bp element, which presumably contains one or more binding sites for Deformed cofactors. We have isolated a novel protein from Drosophila nuclear extracts which binds specifically to a site in this second region. This protein, which we call DEAF-1 (Deformed epidermal autoregulatory factor-1), contains three conserved domains. One of these includes a cysteine repeat motif that is similar to a motif found in Drosophila Nervy and the human MTG8 proto-oncoprotein, and another matches a region of Drosophila Trithorax. Mutations in the response element designed to improve binding to DEAF-1 in vitro resulted in increased embryonic expression. Conversely, small mutations designed to diminish binding to DEAF-1 resulted in reduced expression of the element. Thus, DEAF-1 is likely to contribute to the functional activity, and perhaps to the homeotic specificity, of this response element. Consistent with this hypothesis, we have discovered DEAF-1 binding sites in other Deformed response elements.
Full text
PDFImages in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Affolter M., Percival-Smith A., Müller M., Leupin W., Gehring W. J. DNA binding properties of the purified Antennapedia homeodomain. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4093–4097. doi: 10.1073/pnas.87.11.4093. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Biggin M. D., Tjian R. Transcription factors that activate the Ultrabithorax promoter in developmentally staged extracts. Cell. 1988 Jun 3;53(5):699–711. doi: 10.1016/0092-8674(88)90088-8. [DOI] [PubMed] [Google Scholar]
- Brown N. H., Kafatos F. C. Functional cDNA libraries from Drosophila embryos. J Mol Biol. 1988 Sep 20;203(2):425–437. doi: 10.1016/0022-2836(88)90010-1. [DOI] [PubMed] [Google Scholar]
- Chadwick R., McGinnis W. Temporal and spatial distribution of transcripts from the Deformed gene of Drosophila. EMBO J. 1987 Mar;6(3):779–789. doi: 10.1002/j.1460-2075.1987.tb04820.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chan S. K., Jaffe L., Capovilla M., Botas J., Mann R. S. The DNA binding specificity of Ultrabithorax is modulated by cooperative interactions with extradenticle, another homeoprotein. Cell. 1994 Aug 26;78(4):603–615. doi: 10.1016/0092-8674(94)90525-8. [DOI] [PubMed] [Google Scholar]
- Chang C. P., Shen W. F., Rozenfeld S., Lawrence H. J., Largman C., Cleary M. L. Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins. Genes Dev. 1995 Mar 15;9(6):663–674. doi: 10.1101/gad.9.6.663. [DOI] [PubMed] [Google Scholar]
- Desplan C., Theis J., O'Farrell P. H. The sequence specificity of homeodomain-DNA interaction. Cell. 1988 Sep 23;54(7):1081–1090. doi: 10.1016/0092-8674(88)90123-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dessain S., Gross C. T., Kuziora M. A., McGinnis W. Antp-type homeodomains have distinct DNA binding specificities that correlate with their different regulatory functions in embryos. EMBO J. 1992 Mar;11(3):991–1002. doi: 10.1002/j.1460-2075.1992.tb05138.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ekker S. C., Jackson D. G., von Kessler D. P., Sun B. I., Young K. E., Beachy P. A. The degree of variation in DNA sequence recognition among four Drosophila homeotic proteins. EMBO J. 1994 Aug 1;13(15):3551–3560. doi: 10.1002/j.1460-2075.1994.tb06662.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Elfring L. K., Deuring R., McCallum C. M., Peterson C. L., Tamkun J. W. Identification and characterization of Drosophila relatives of the yeast transcriptional activator SNF2/SWI2. Mol Cell Biol. 1994 Apr;14(4):2225–2234. doi: 10.1128/mcb.14.4.2225. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Erickson P. F., Robinson M., Owens G., Drabkin H. A. The ETO portion of acute myeloid leukemia t(8;21) fusion transcript encodes a highly evolutionarily conserved, putative transcription factor. Cancer Res. 1994 Apr 1;54(7):1782–1786. [PubMed] [Google Scholar]
- Feinstein P. G., Kornfeld K., Hogness D. S., Mann R. S. Identification of homeotic target genes in Drosophila melanogaster including nervy, a proto-oncogene homologue. Genetics. 1995 Jun;140(2):573–586. doi: 10.1093/genetics/140.2.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Florence B., Handrow R., Laughon A. DNA-binding specificity of the fushi tarazu homeodomain. Mol Cell Biol. 1991 Jul;11(7):3613–3623. doi: 10.1128/mcb.11.7.3613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hanes S. D., Riddihough G., Ish-Horowicz D., Brent R. Specific DNA recognition and intersite spacing are critical for action of the bicoid morphogen. Mol Cell Biol. 1994 May;14(5):3364–3375. doi: 10.1128/mcb.14.5.3364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hatfull G. F., Grindley N. D. Analysis of gamma delta resolvase mutants in vitro: evidence for an interaction between serine-10 of resolvase and site I of res. Proc Natl Acad Sci U S A. 1986 Aug;83(15):5429–5433. doi: 10.1073/pnas.83.15.5429. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoey T., Levine M. Divergent homeo box proteins recognize similar DNA sequences in Drosophila. Nature. 1988 Apr 28;332(6167):858–861. doi: 10.1038/332858a0. [DOI] [PubMed] [Google Scholar]
- Johnson F. B., Parker E., Krasnow M. A. Extradenticle protein is a selective cofactor for the Drosophila homeotics: role of the homeodomain and YPWM amino acid motif in the interaction. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):739–743. doi: 10.1073/pnas.92.3.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kadereit S., Gewert D. R., Galabru J., Hovanessian A. G., Meurs E. F. Molecular cloning of two new interferon-induced, highly related nuclear phosphoproteins. J Biol Chem. 1993 Nov 15;268(32):24432–24441. [PubMed] [Google Scholar]
- Kadonaga J. T., Tjian R. Affinity purification of sequence-specific DNA binding proteins. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5889–5893. doi: 10.1073/pnas.83.16.5889. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kennison J. A., Tamkun J. W. Dosage-dependent modifiers of polycomb and antennapedia mutations in Drosophila. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8136–8140. doi: 10.1073/pnas.85.21.8136. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kennison J. A. Transcriptional activation of Drosophila homeotic genes from distant regulatory elements. Trends Genet. 1993 Mar;9(3):75–79. doi: 10.1016/0168-9525(93)90227-9. [DOI] [PubMed] [Google Scholar]
- Kenyon C. If birds can fly, why can't we? Homeotic genes and evolution. Cell. 1994 Jul 29;78(2):175–180. doi: 10.1016/0092-8674(94)90288-7. [DOI] [PubMed] [Google Scholar]
- Mahaffey J. W., Jones D. F., Hickel J. A., Griswold C. M. Identification and characterization of a gene activated by the deformed homeoprotein. Development. 1993 May;118(1):203–214. doi: 10.1242/dev.118.1.203. [DOI] [PubMed] [Google Scholar]
- Malicki J., Cianetti L. C., Peschle C., McGinnis W. A human HOX4B regulatory element provides head-specific expression in Drosophila embryos. Nature. 1992 Jul 23;358(6384):345–347. doi: 10.1038/358345a0. [DOI] [PubMed] [Google Scholar]
- Mazo A. M., Huang D. H., Mozer B. A., Dawid I. B. The trithorax gene, a trans-acting regulator of the bithorax complex in Drosophila, encodes a protein with zinc-binding domains. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2112–2116. doi: 10.1073/pnas.87.6.2112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McGinnis W., Krumlauf R. Homeobox genes and axial patterning. Cell. 1992 Jan 24;68(2):283–302. doi: 10.1016/0092-8674(92)90471-n. [DOI] [PubMed] [Google Scholar]
- Merrill V. K., Turner F. R., Kaufman T. C. A genetic and developmental analysis of mutations in the Deformed locus in Drosophila melanogaster. Dev Biol. 1987 Aug;122(2):379–395. doi: 10.1016/0012-1606(87)90303-4. [DOI] [PubMed] [Google Scholar]
- Miyoshi H., Kozu T., Shimizu K., Enomoto K., Maseki N., Kaneko Y., Kamada N., Ohki M. The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript. EMBO J. 1993 Jul;12(7):2715–2721. doi: 10.1002/j.1460-2075.1993.tb05933.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mohler J., Mahaffey J. W., Deutsch E., Vani K. Control of Drosophila head segment identity by the bZIP homeotic gene cnc. Development. 1995 Jan;121(1):237–247. doi: 10.1242/dev.121.1.237. [DOI] [PubMed] [Google Scholar]
- Owens G. P., Hahn W. E., Cohen J. J. Identification of mRNAs associated with programmed cell death in immature thymocytes. Mol Cell Biol. 1991 Aug;11(8):4177–4188. doi: 10.1128/mcb.11.8.4177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Peifer M., Wieschaus E. Mutations in the Drosophila gene extradenticle affect the way specific homeo domain proteins regulate segmental identity. Genes Dev. 1990 Jul;4(7):1209–1223. doi: 10.1101/gad.4.7.1209. [DOI] [PubMed] [Google Scholar]
- Pöpperl H., Bienz M., Studer M., Chan S. K., Aparicio S., Brenner S., Mann R. S., Krumlauf R. Segmental expression of Hoxb-1 is controlled by a highly conserved autoregulatory loop dependent upon exd/pbx. Cell. 1995 Jun 30;81(7):1031–1042. doi: 10.1016/s0092-8674(05)80008-x. [DOI] [PubMed] [Google Scholar]
- Regulski M., McGinnis N., Chadwick R., McGinnis W. Developmental and molecular analysis of Deformed; a homeotic gene controlling Drosophila head development. EMBO J. 1987 Mar;6(3):767–777. doi: 10.1002/j.1460-2075.1987.tb04819.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schier A. F., Gehring W. J. Analysis of a fushi tarazu autoregulatory element: multiple sequence elements contribute to enhancer activity. EMBO J. 1993 Mar;12(3):1111–1119. doi: 10.1002/j.1460-2075.1993.tb05752.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schwabe J. W., Klug A. Zinc mining for protein domains. Nat Struct Biol. 1994 Jun;1(6):345–349. doi: 10.1038/nsb0694-345. [DOI] [PubMed] [Google Scholar]
- Sedkov Y., Tillib S., Mizrokhi L., Mazo A. The bithorax complex is regulated by trithorax earlier during Drosophila embryogenesis than is the Antennapedia complex, correlating with a bithorax-like expression pattern of distinct early trithorax transcripts. Development. 1994 Jul;120(7):1907–1917. doi: 10.1242/dev.120.7.1907. [DOI] [PubMed] [Google Scholar]
- Smith D. L., Johnson A. D. A molecular mechanism for combinatorial control in yeast: MCM1 protein sets the spacing and orientation of the homeodomains of an alpha 2 dimer. Cell. 1992 Jan 10;68(1):133–142. doi: 10.1016/0092-8674(92)90212-u. [DOI] [PubMed] [Google Scholar]
- Tautz D., Pfeifle C. A non-radioactive in situ hybridization method for the localization of specific RNAs in Drosophila embryos reveals translational control of the segmentation gene hunchback. Chromosoma. 1989 Aug;98(2):81–85. doi: 10.1007/BF00291041. [DOI] [PubMed] [Google Scholar]
- Tripoulas N. A., Hersperger E., La Jeunesse D., Shearn A. Molecular genetic analysis of the Drosophila melanogaster gene absent, small or homeotic discs1 (ash1). Genetics. 1994 Aug;137(4):1027–1038. doi: 10.1093/genetics/137.4.1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vincent J. P., Kassis J. A., O'Farrell P. H. A synthetic homeodomain binding site acts as a cell type specific, promoter specific enhancer in Drosophila embryos. EMBO J. 1990 Aug;9(8):2573–2578. doi: 10.1002/j.1460-2075.1990.tb07438.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Walker S., Hayes S., O'Hare P. Site-specific conformational alteration of the Oct-1 POU domain-DNA complex as the basis for differential recognition by Vmw65 (VP16). Cell. 1994 Dec 2;79(5):841–852. doi: 10.1016/0092-8674(94)90073-6. [DOI] [PubMed] [Google Scholar]
- Walter J., Dever C. A., Biggin M. D. Two homeo domain proteins bind with similar specificity to a wide range of DNA sites in Drosophila embryos. Genes Dev. 1994 Jul 15;8(14):1678–1692. doi: 10.1101/gad.8.14.1678. [DOI] [PubMed] [Google Scholar]
- Zeng C., Pinsonneault J., Gellon G., McGinnis N., McGinnis W. Deformed protein binding sites and cofactor binding sites are required for the function of a small segment-specific regulatory element in Drosophila embryos. EMBO J. 1994 May 15;13(10):2362–2377. doi: 10.1002/j.1460-2075.1994.tb06520.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- van Dijk M. A., Murre C. extradenticle raises the DNA binding specificity of homeotic selector gene products. Cell. 1994 Aug 26;78(4):617–624. doi: 10.1016/0092-8674(94)90526-6. [DOI] [PubMed] [Google Scholar]