Abstract
The initial genomic response to serum growth factors is the transcriptional activation of a set of immediate-early genes. Serum-induced transcriptional activation of several of these genes involves the formation of a ternary complex that includes the serum response factor (SRF), a 62 kDa ternary complex factor (TCF) and a serum response element (SRE). TCF alone does not bind the SRE of the protooncogene c-fos, but requires the prior assembly of the SRF-SRE binary complex for it to be recruited into a ternary complex. Here we show that this SRF-SRE binary complex is not an obligatory prerequisite for the formation of a serum responsive ternary complex. We demonstrate that Elk-1, which has properties of TCF can recruit SRF into a ternary complex on elements that do not support formation of the SRF-DNA binary complex. We also show that for two immediate-early genes, pip92 and nur77, formation of the ternary complex may occur without the prior assembly of SRF-DNA binary complex. Finally, we show that the ability of different sequences to support formation of Elk-l-SRF-DNA ternary complex in vitro correlates with their ability to respond to serum growth factors in vivo. Our results suggest that a much broader range of DNA sequences than the consensus SRF and TCF binding sites can support ternary complex formation, and by inference, serum induction. Possible implications of these results are discussed.
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- Almendral J. M., Sommer D., Macdonald-Bravo H., Burckhardt J., Perera J., Bravo R. Complexity of the early genetic response to growth factors in mouse fibroblasts. Mol Cell Biol. 1988 May;8(5):2140–2148. doi: 10.1128/mcb.8.5.2140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Charles C. H., Simske J. S., O'Brien T. P., Lau L. F. Pip92: a short-lived, growth factor-inducible protein in BALB/c 3T3 and PC12 cells. Mol Cell Biol. 1990 Dec;10(12):6769–6774. doi: 10.1128/mcb.10.12.6769. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chavrier P., Janssen-Timmen U., Mattéi M. G., Zerial M., Bravo R., Charnay P. Structure, chromosome location, and expression of the mouse zinc finger gene Krox-20: multiple gene products and coregulation with the proto-oncogene c-fos. Mol Cell Biol. 1989 Feb;9(2):787–797. doi: 10.1128/mcb.9.2.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Christy B., Nathans D. Functional serum response elements upstream of the growth factor-inducible gene zif268. Mol Cell Biol. 1989 Nov;9(11):4889–4895. doi: 10.1128/mcb.9.11.4889. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dalton S., Treisman R. Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element. Cell. 1992 Feb 7;68(3):597–612. doi: 10.1016/0092-8674(92)90194-h. [DOI] [PubMed] [Google Scholar]
- Graham R., Gilman M. Distinct protein targets for signals acting at the c-fos serum response element. Science. 1991 Jan 11;251(4990):189–192. doi: 10.1126/science.1898992. [DOI] [PubMed] [Google Scholar]
- Gégonne A., Bosselut R., Bailly R. A., Ghysdael J. Synergistic activation of the HTLV1 LTR Ets-responsive region by transcription factors Ets1 and Sp1. EMBO J. 1993 Mar;12(3):1169–1178. doi: 10.1002/j.1460-2075.1993.tb05758.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hazel T. G., Nathans D., Lau L. F. A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8444–8448. doi: 10.1073/pnas.85.22.8444. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Herschman H. R. Primary response genes induced by growth factors and tumor promoters. Annu Rev Biochem. 1991;60:281–319. doi: 10.1146/annurev.bi.60.070191.001433. [DOI] [PubMed] [Google Scholar]
- Hill C. S., Marais R., John S., Wynne J., Dalton S., Treisman R. Functional analysis of a growth factor-responsive transcription factor complex. Cell. 1993 Apr 23;73(2):395–406. doi: 10.1016/0092-8674(93)90238-l. [DOI] [PubMed] [Google Scholar]
- Hill C. S., Treisman R. Differential activation of c-fos promoter elements by serum, lysophosphatidic acid, G proteins and polypeptide growth factors. EMBO J. 1995 Oct 16;14(20):5037–5047. doi: 10.1002/j.1460-2075.1995.tb00186.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hill C. S., Wynne J., Treisman R. Serum-regulated transcription by serum response factor (SRF): a novel role for the DNA binding domain. EMBO J. 1994 Nov 15;13(22):5421–5432. doi: 10.1002/j.1460-2075.1994.tb06877.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hill C. S., Wynne J., Treisman R. Serum-regulated transcription by serum response factor (SRF): a novel role for the DNA binding domain. EMBO J. 1994 Nov 15;13(22):5421–5432. doi: 10.1002/j.1460-2075.1994.tb06877.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hipskind R. A., Rao V. N., Mueller C. G., Reddy E. S., Nordheim A. Ets-related protein Elk-1 is homologous to the c-fos regulatory factor p62TCF. Nature. 1991 Dec 19;354(6354):531–534. doi: 10.1038/354531a0. [DOI] [PubMed] [Google Scholar]
- Johansen F. E., Prywes R. Two pathways for serum regulation of the c-fos serum response element require specific sequence elements and a minimal domain of serum response factor. Mol Cell Biol. 1994 Sep;14(9):5920–5928. doi: 10.1128/mcb.14.9.5920. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kawamoto T., Makino K., Orita S., Nakata A., Kakunaga T. DNA bending and binding factors of the human beta-actin promoter. Nucleic Acids Res. 1989 Jan 25;17(2):523–537. doi: 10.1093/nar/17.2.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kuang A. A., Novak K. D., Kang S. M., Bruhn K., Lenardo M. J. Interaction between NF-kappa B- and serum response factor-binding elements activates an interleukin-2 receptor alpha-chain enhancer specifically in T lymphocytes. Mol Cell Biol. 1993 Apr;13(4):2536–2545. doi: 10.1128/mcb.13.4.2536. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Latinkic B. V., O'Brien T. P., Lau L. F. Promoter function and structure of the growth factor-inducible immediate early gene cyr61. Nucleic Acids Res. 1991 Jun 25;19(12):3261–3267. doi: 10.1093/nar/19.12.3261. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Latinkić B. V., Lau L. F. Transcriptional activation of the immediate early gene pip92 by serum growth factors requires both Ets and CArG-like elements. J Biol Chem. 1994 Sep 16;269(37):23163–23170. [PubMed] [Google Scholar]
- Leung S., Miyamoto N. G. Point mutational analysis of the human c-fos serum response factor binding site. Nucleic Acids Res. 1989 Feb 11;17(3):1177–1195. doi: 10.1093/nar/17.3.1177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marais R., Wynne J., Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell. 1993 Apr 23;73(2):381–393. doi: 10.1016/0092-8674(93)90237-k. [DOI] [PubMed] [Google Scholar]
- Nye J. A., Petersen J. M., Gunther C. V., Jonsen M. D., Graves B. J. Interaction of murine ets-1 with GGA-binding sites establishes the ETS domain as a new DNA-binding motif. Genes Dev. 1992 Jun;6(6):975–990. doi: 10.1101/gad.6.6.975. [DOI] [PubMed] [Google Scholar]
- Pollock R., Treisman R. A sensitive method for the determination of protein-DNA binding specificities. Nucleic Acids Res. 1990 Nov 11;18(21):6197–6204. doi: 10.1093/nar/18.21.6197. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pollock R., Treisman R. Human SRF-related proteins: DNA-binding properties and potential regulatory targets. Genes Dev. 1991 Dec;5(12A):2327–2341. doi: 10.1101/gad.5.12a.2327. [DOI] [PubMed] [Google Scholar]
- Pollock R., Treisman R. Human SRF-related proteins: DNA-binding properties and potential regulatory targets. Genes Dev. 1991 Dec;5(12A):2327–2341. doi: 10.1101/gad.5.12a.2327. [DOI] [PubMed] [Google Scholar]
- Rao V. N., Reddy E. S. A divergent ets-related protein, elk-1, recognizes similar c-ets-1 proto-oncogene target sequences and acts as a transcriptional activator. Oncogene. 1992 Jan;7(1):65–70. [PubMed] [Google Scholar]
- Rao V. N., Reddy E. S. elk-1 domains responsible for autonomous DNA binding, SRE:SRF interaction and negative regulation of DNA binding. Oncogene. 1992 Nov;7(11):2335–2340. [PubMed] [Google Scholar]
- Rivera V. M., Greenberg M. E. Growth factor-induced gene expression: the ups and downs of c-fos regulation. New Biol. 1990 Sep;2(9):751–758. [PubMed] [Google Scholar]
- Ryseck R. P., Macdonald-Bravo H., Mattéi M. G., Ruppert S., Bravo R. Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor. EMBO J. 1989 Nov;8(11):3327–3335. doi: 10.1002/j.1460-2075.1989.tb08494.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schröter H., Mueller C. G., Meese K., Nordheim A. Synergism in ternary complex formation between the dimeric glycoprotein p67SRF, polypeptide p62TCF and the c-fos serum response element. EMBO J. 1990 Apr;9(4):1123–1130. doi: 10.1002/j.1460-2075.1990.tb08218.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shaw P. E., Schröter H., Nordheim A. The ability of a ternary complex to form over the serum response element correlates with serum inducibility of the human c-fos promoter. Cell. 1989 Feb 24;56(4):563–572. doi: 10.1016/0092-8674(89)90579-5. [DOI] [PubMed] [Google Scholar]
- Shore P., Sharrocks A. D. The transcription factors Elk-1 and serum response factor interact by direct protein-protein contacts mediated by a short region of Elk-1. Mol Cell Biol. 1994 May;14(5):3283–3291. doi: 10.1128/mcb.14.5.3283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Treisman R. Identification and purification of a polypeptide that binds to the c-fos serum response element. EMBO J. 1987 Sep;6(9):2711–2717. doi: 10.1002/j.1460-2075.1987.tb02564.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Treisman R., Marais R., Wynne J. Spatial flexibility in ternary complexes between SRF and its accessory proteins. EMBO J. 1992 Dec;11(12):4631–4640. doi: 10.1002/j.1460-2075.1992.tb05565.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Treisman R. Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Dev. 1994 Feb;4(1):96–101. doi: 10.1016/0959-437x(94)90097-3. [DOI] [PubMed] [Google Scholar]
- Treisman R. The SRE: a growth factor responsive transcriptional regulator. Semin Cancer Biol. 1990 Feb;1(1):47–58. [PubMed] [Google Scholar]
- Treisman R. The serum response element. Trends Biochem Sci. 1992 Oct;17(10):423–426. doi: 10.1016/0968-0004(92)90013-y. [DOI] [PubMed] [Google Scholar]
- Wasylyk B., Wasylyk C., Flores P., Begue A., Leprince D., Stehelin D. The c-ets proto-oncogenes encode transcription factors that cooperate with c-Fos and c-Jun for transcriptional activation. Nature. 1990 Jul 12;346(6280):191–193. doi: 10.1038/346191a0. [DOI] [PubMed] [Google Scholar]
- Williams G. T., Lau L. F. Activation of the inducible orphan receptor gene nur77 by serum growth factors: dissociation of immediate-early and delayed-early responses. Mol Cell Biol. 1993 Oct;13(10):6124–6136. doi: 10.1128/mcb.13.10.6124. [DOI] [PMC free article] [PubMed] [Google Scholar]