DNA Binding Specificity Studies of Four ETS Proteins Support an Indirect Read-out Mechanism of Protein-DNA Recognition

Members of the ETS family of transcription factors are involved in several developmental and physiological processes, and, when overexpressed or misexpressed, can contribute to a variety of cancers. Each family member has a conserved DNA-binding domain that recognizes DNA sequences containing a G-G-A trinucleotide. Discrimination between potential ETS-binding sites appears to be governed by both the nucleotides flanking the G-G-A sequence and protein-protein interactions. We have used an adaptation of the “length-encoded multiplex” approach (Desjarlais, J. R., and Berg, J. M. (1994) Proc. Natl. Acad. Sci. U. S. A.91, 11099–11103) to define DNA binding specificities for four ETS proteins: Fli-1, SAP-1, PU.1, and TEL. Our results support a model in which cooperative effects among neighboring bases flanking the central G-G-A site contribute to the formation of stable ETS/DNA complexes. These results are consistent with a mechanism for specific DNA binding that is partially governed by an indirect read-out of the DNA sequence, in which a sequence-specific DNA conformation is sensed or induced. Members of the ETS family of transcription factors are involved in several developmental and physiological processes, and, when overexpressed or misexpressed, can contribute to a variety of cancers. Each family member has a conserved DNA-binding domain that recognizes DNA sequences containing a G-G-A trinucleotide. Discrimination between potential ETS-binding sites appears to be governed by both the nucleotides flanking the G-G-A sequence and protein-protein interactions. We have used an adaptation of the “length-encoded multiplex” approach (Desjarlais, J. R., and Berg, J. M. (1994) Proc. Natl. Acad. Sci. U. S. A.91, 11099–11103) to define DNA binding specificities for four ETS proteins: Fli-1, SAP-1, PU.1, and TEL. Our results support a model in which cooperative effects among neighboring bases flanking the central G-G-A site contribute to the formation of stable ETS/DNA complexes. These results are consistent with a mechanism for specific DNA binding that is partially governed by an indirect read-out of the DNA sequence, in which a sequence-specific DNA conformation is sensed or induced. The ETS gene family encodes a group of more than 45 proteins, each with a highly conserved 85-amino acid DNA-binding domain initially mapped to v-ets-1, the member for which this group is named (1Sharrocks A.D. Brown A.L. Ling Y. Yates P.R. Int. J. Biochem. Cell Biol. 1997; 29: 1371-1387Crossref PubMed Scopus (279) Google Scholar, 2Wasylyk B. Hahn S.L. Giovane A. Eur. J. Biochem. 1993; 211: 7-18Crossref PubMed Scopus (809) Google Scholar). Members of the family identified to date share between 36 and 97% sequence identity with the Ets-1 DNA-binding domain and have been found in species ranging from lower invertebrates to humans. ETS family members can function as transcriptional activators or repressors and are involved in a wide range of tissue specific developmental processes. In humans, they are involved in hematopoiesis (3Barton K. Muthusamy N. Fischer C. Ting C.N. Walunas T.L. Lanier L.L. Leiden J.M. Immunity. 1998; 9: 555-563Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 4Scott E. Simon MC. Anastasi J. Singh H. Science. 1994; 265: 1573-1577Crossref PubMed Scopus (1266) Google Scholar, 5Wang L.C. Swat W. Fujiwara Y. Davidson L. Visvader J. Kuo F. Alt F.W. Gilliland D.G. Golub T.R. Orkin S.H. Genes Dev. 1998; 12: 2392-2402Crossref PubMed Scopus (217) Google Scholar), ossification (6Kola I. Brookes S. Green A.R. Garber R. Tymms M. Papas T.S. Seth A. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 7588-7592Crossref PubMed Scopus (216) Google Scholar, 7Maroulakou I.G. Papas T.S. Green J.E. Oncogene. 1994; 9: 1551-1565PubMed Google Scholar), myogenisis (8Taylor J.M. Dupont-Versteegden E.E. Davies J.D. Hassell J.A. Houle J.D. Gurley C.M. Peterson C.A. Mol. Cell. Biol. 1997; 17: 5550-5558Crossref PubMed Scopus (34) Google Scholar), and angiogenesis (9Iwasaka C. Tanaka K. Abe M. Sato Y. J. Cell Phys. 1996; 169: 522-531Crossref PubMed Scopus (271) Google Scholar, 10Oda N. Abe M. Sato Y. J. Cell Phys. 1999; 178: 121-132Crossref PubMed Scopus (192) Google Scholar). ETS proteins have also been implicated in several types of cancer and other human diseases (11Dittmer J. Nordheim A. Biochim. Biophys. Acta. 1998; 1377: F1-F11PubMed Google Scholar). Because ETS proteins have overlapping DNA binding specificities and because their expression is often tissue type-specific, inappropriate expression or altered forms of a given ETS protein will likely activate genes that are normally not expressed. Thus, an understanding of the sequence specificity of ETS proteins is important for understanding the mechanism of deregulation in ETS-related cancers. All ETS DNA-binding domains recognize a purine-rich G-G-A sequence, yet each family member has specificity for characteristic bases flanking this segment (2Wasylyk B. Hahn S.L. Giovane A. Eur. J. Biochem. 1993; 211: 7-18Crossref PubMed Scopus (809) Google Scholar, 12Bemark M. Martensson A. Liberg D. Leanderson T. J. Biol. Chem. 1999; 274: 10259-10267Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 13Brown L.A. Amores A. Schilling T.F. Jowett T. Baert J.L. de Launoit Y. Sharrocks A.D. Oncogene. 1998; 17: 93-104Crossref PubMed Scopus (54) Google Scholar, 14John S. Marais R. Child R. Light Y. Leonard W.J. J. Exp. Med. 1996; 183: 743-750Crossref PubMed Scopus (30) Google Scholar, 15Li S.L. Schlegel W. Valente A.J. Clark R.A. J. Biol. Chem. 1999; 274: 32453-32460Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 16Mao X. Miesfeldt S. Yang H. Leiden J.M. Thompson C.B. J. Biol. Chem. 1994; 269: 18216-18222Abstract Full Text PDF PubMed Google Scholar, 17Pio F. Assa-Munt N. Yguerabide J. Maki R.A. Protein Sci. 1999; 8: 2098-2109Crossref PubMed Scopus (19) Google Scholar, 18Ray-Gallet D. Mao C. Tavitian A. Moreau-Gachelin F. Oncogene. 1995; 11: 303-313PubMed Google Scholar, 19Shore P. Sharrocks A.D. Nucleic Acids Res. 1995; 23: 4698-4706Crossref PubMed Scopus (77) Google Scholar). The recent solution and crystal structures of the ETS domains of Fli-1 (20Liang H. Mao X. Olejniczak E.T. Nettesheim D.G., Yu, L. Meadows R.P. Thompson C.B. Fesik S.W. Nat. Struct. Biol. 1994; 1: 871-875Crossref PubMed Scopus (101) Google Scholar), Ets-1 (21Donaldson L.W. Petersen J.M. Graves B.J. McIntosh L.P. EMBO J. 1996; 15: 125-134Crossref PubMed Scopus (134) Google Scholar, 22Werner M.H. Clore M. Fisher C.L. Fisher R.J. Trinh L. Shiloach J. Gronenborn A.M. Cell. 1995; 83: 761-771Abstract Full Text PDF PubMed Scopus (110) Google Scholar, 23Werner M.H. Clore G.M. Fisher C.L. Fisher R.J. Trinh L. Shiloach J. Gronenborn A.M. J. Biomol. NMR. 1997; 10: 317-328Crossref PubMed Scopus (59) Google Scholar), PU.1 (24Kodandapani R. Pio F. Ni C.Z. Piccialli G. Klemsz M. McKercher S. Maki R.A. Ely K.R. Nature. 1996; 830: 456-460Crossref Scopus (266) Google Scholar), GABPα/β (25Batchelor A.H. Piper D.E. de la Brousse F.C. McKnight S.L. Wolberger C. Science. 1998; 279: 1037-1041Crossref PubMed Scopus (266) Google Scholar), SAP-1 (26Mo Y. Vaessen B. Johnston K. Marmorstein R. Mol. Cell. 1998; 2: 201-212Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar), and Elk-1 (27Mo Y. Vaessen B. Johnston K. Marmorstein R. Nat. Struct. Biol. 2000; 7: 292-297Crossref PubMed Scopus (81) Google Scholar) have established that the ETS proteins constitute a subgroup within the super-family of “winged helix-loop-helix” DNA-binding proteins. Structures of these six domains complexed with DNA show that helix-3 lies in the major groove centered at the G-G-A recognition site. In the crystal structures of PU.1 (24Kodandapani R. Pio F. Ni C.Z. Piccialli G. Klemsz M. McKercher S. Maki R.A. Ely K.R. Nature. 1996; 830: 456-460Crossref Scopus (266) Google Scholar), GABPα (25Batchelor A.H. Piper D.E. de la Brousse F.C. McKnight S.L. Wolberger C. Science. 1998; 279: 1037-1041Crossref PubMed Scopus (266) Google Scholar), SAP-1 (26Mo Y. Vaessen B. Johnston K. Marmorstein R. Mol. Cell. 1998; 2: 201-212Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar), and Elk-1 (27Mo Y. Vaessen B. Johnston K. Marmorstein R. Nat. Struct. Biol. 2000; 7: 292-297Crossref PubMed Scopus (81) Google Scholar), two conserved Arg residues within helix 3 make direct hydrogen bonds with the bases of the G-G-A motif. Importantly, the pattern of hydrogen bonds from these conserved arginines is not the same in the different high resolution crystal structures. This suggests that the ETS domain may have some degree of flexibility and diversity in its mode of interaction with DNA. Regions of the ETS domain flanking helix-3 interact with phosphates along the minor groove both upstream and downstream of the G-G-A element, further stabilizing the complex and bending the DNA around the protein. Variation in DNA bending from 11 to 28° for the SAP-1 and PU.1 complexes, respectively, and few unique direct contacts to the bases flanking G-G-A suggest a possible “indirect read-out” mechanism of DNA recognition, wherein the ETS domain recognizes a that is or in DNA. This model is in to a read-out” mechanism of DNA binding in which protein residues recognize and interact with unique within an ETS-binding site. In both contacts between the protein and the DNA. the DNA-binding sequence specificity within the ETS family of transcription have the specificity of four ETS domains the same The ETS domains of Fli-1 and SAP-1 are the of the proteins and from and and PU.1 and is identity between the ETS domains of and Fli-1, SAP-1, and PU.1 because the structures of these proteins to DNA have been (20Liang H. Mao X. Olejniczak E.T. Nettesheim D.G., Yu, L. Meadows R.P. Thompson C.B. Fesik S.W. Nat. Struct. Biol. 1994; 1: 871-875Crossref PubMed Scopus (101) Google R. Pio F. Ni C.Z. Piccialli G. Klemsz M. McKercher S. Maki R.A. Ely K.R. Nature. 1996; 830: 456-460Crossref Scopus (266) Google Scholar, Y. Vaessen B. Johnston K. Marmorstein R. Mol. Cell. 1998; 2: 201-212Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar), and is a of their DNA binding or specificity have been for TEL. We have used an the J.M. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar), which can the DNA binding specificity of proteins. Our in DNA binding specificity among these four ETS proteins and support an indirect read-out mechanism of These results have important for understanding the of ETS proteins in transcriptional DNA from Fli-1 human SAP-1 PU.1 and human the F.W. J. Mol. Biol. PubMed Scopus Google Scholar) expression and The the ETS protein with an by a site. in and The by of protein in and solution at The of protein range from to for the and from each have a G-G-A ETS-binding sequence by six for a that is The identity and of the to the G-G-A a the G-G-A in with and six flanking The sequence of the The other by or two bases to from the sequence by The of to be for binding by the ETS the results binding to the which a results for the and a of further in E. F. T. Scholar). identified by the in solution for and to or by in of and a for at and DNA of the DNA by of each and in which a downstream and upstream of the G-G-A The altered and The in the with and of by at for from the solution the The to for and to to with DNA and an of to the by to for and The and their from for binding and C. the with The and as with the in with by to for and to The ETS protein of with of in of binding for at and or and by the of of the and for at and at for and at The of proteins used in than of the The a at for at and DNA by and from the DNA as and to of the to of and to for a by with of for 3 the as a in for at W. in DNA solution to and for at a and with by the a of by to the in the The of each by the of the by the of four for the The in with to at from the the J.M. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar), is the is the is the of and is the of Y. from with of protein in binding to as a and at for at and a by by as a function of protein by the to the is the of DNA and are the of protein and respectively, and is the from for each to the of complex is the and is the The is by We the of a “length-encoded multiplex” of J.M. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar) for the of ETS proteins for each of six upstream and downstream of the G-G-A ETS recognition Each of the six sites for The of the to the G-G-A or and its identity or at the to as a for DNA DNA This the is and within the The ETS proteins of with the of and the and a highly The of each of from the of than of the the pattern of the the same of protein This pattern different from the of the and from the In the of the and is an at and is at for each ETS protein the results for the by the of these their to of the and results from the of that an is to a at This suggests the of the that encodes at the may have been for the other the pattern at the not altered by the The by as a the in the the to the of to the from the and its in the are also in not Because binding of the not to be likely not from binding from the of G-G-A sites within the in the to and a sequence for each ETS and have with proteins an at and at the of the for the that two are of sequences from and bases with than are with the in bases that are at a site of the of the a than of the that have to the sequences for Fli-1 X. Miesfeldt S. Yang H. Leiden J.M. Thompson C.B. J. Biol. Chem. 1994; 269: 18216-18222Abstract Full Text PDF PubMed Google Scholar), SAP-1 P. Sharrocks A.D. Nucleic Acids Res. 1995; 23: 4698-4706Crossref PubMed Scopus (77) Google Scholar), and PU.1 D. Mao C. Tavitian A. Moreau-Gachelin F. Oncogene. 1995; 11: 303-313PubMed Google Scholar) are the the sequences bases from the sequences of the PU.1, a sequence also from the in sequences in the the sequences to from other to ETS-binding sites identified in other from for Fli-1, SAP-1, and PU.1 are in the of high sequences from a of M. Mol. Biol. 1994; PubMed Scopus Google Scholar). a both with with the sequences more at between the two are for bases at and These are likely to the different and may important of DNA sequences with high the of a to complex of the sequence sequence from the of PU.1 sequences is also in that have been to PU.1 in the PU.1 binding element, G-G-A or as a The sequence from the sequences from both and at the the that sequence are to for and with six ETS binding sites and The a high sequence, the other from this sequence by or two of with the for the complex This also with the for for binding to the with the sequence or as to the from Brown L.A. Amores A. Schilling T.F. Jowett T. Baert J.L. de Launoit Y. Sharrocks A.D. Oncogene. 1998; 17: 93-104Crossref PubMed Scopus (54) Google Scholar, L.A. Yang S.H. A. A. Sharrocks A.D. Oncogene. 1999; PubMed Scopus Google Scholar) also support this is by a recent of PU.1 binding to ETS-binding sites in the of and a gene to binding S.L. Schlegel W. Valente A.J. Clark R.A. J. Biol. Chem. 1999; 274: 32453-32460Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). The in the binding site a of in than each of the in the binding These of the and suggest that the between and between the between and in for and to a high for the complex are also in a for the complex are also of the approach is its potential to the of a protein for a given binding site J.M. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar). This is possible each to complex In this the in with the altered bases are and the in is the and for specific DNA be possible to between a direct read-out mechanism of DNA binding and a mechanism in which of bases in the recognition of specific ETS proteins. the and than This of the to the in with a suggests that bases not contribute to complex The suggest that the sequence at each may be important in ETS interactions. this the of high binding sites identified for PU.1 and Fli-1 the D. Mao C. Tavitian A. Moreau-Gachelin F. Oncogene. 1995; 11: 303-313PubMed Google Scholar). the of bases at the and for that have or at the site. The Fisher that the at and is with the or at at is often by bases at both the and the other at is often by a at and a or at the highly is also for Fli-1 at the and the and are of bases in high PU.1 and Fli-1 binding of bases at the and in PU.1 is by a or at the D. Mao C. Tavitian A. Moreau-Gachelin F. Oncogene. 1995; 11: 303-313PubMed Google Scholar). is a between the at the and of by Fli-1 X. Miesfeldt S. Yang H. Leiden J.M. Thompson C.B. J. Biol. Chem. 1994; 269: 18216-18222Abstract Full Text PDF PubMed Google Scholar). from the sequences of the in the in a The of bases at the and in PU.1 is by a or at the D. Mao C. Tavitian A. Moreau-Gachelin F. Oncogene. 1995; 11: 303-313PubMed Google Scholar). is a between the at the and of by Fli-1 X. Miesfeldt S. Yang H. Leiden J.M. Thompson C.B. J. Biol. Chem. 1994; 269: 18216-18222Abstract Full Text PDF PubMed Google Scholar). from the sequences of the in the We have a of the DNA binding specificity of four ETS domain proteins several We that the DNA binding specificity can the specificity of ETS proteins to date have used forms of to high which are to a binding sequence for a given protein M. Martensson A. Liberg D. Leanderson T. J. Biol. Chem. 1999; 274: 10259-10267Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 13Brown L.A. Amores A. Schilling T.F. Jowett T. Baert J.L. de Launoit Y. Sharrocks A.D. Oncogene. 1998; 17: 93-104Crossref PubMed Scopus (54) Google Scholar, 14John S. Marais R. Child R. Light Y. Leonard W.J. J. Exp. Med. 1996; 183: 743-750Crossref PubMed Scopus (30) Google Scholar, 16Mao X. Miesfeldt S. Yang H. Leiden J.M. Thompson C.B. J. Biol. Chem. 1994; 269: 18216-18222Abstract Full Text PDF PubMed Google Scholar, 18Ray-Gallet D. Mao C. Tavitian A. Moreau-Gachelin F. Oncogene. 1995; 11: 303-313PubMed Google Scholar, 19Shore P. Sharrocks A.D. Nucleic Acids Res. 1995; 23: 4698-4706Crossref PubMed Scopus (77) Google Scholar, McKnight S.L. Genes Dev. PubMed Scopus Google Scholar, R.J. G. A. Papas T.S. Oncogene. Google Scholar, J.A. Petersen J.M. Graves B.J. Genes Dev. PubMed Scopus Google Scholar, Cell. Full Text PDF PubMed Scopus Google Scholar, J. Nucleic Acids Res. PubMed Scopus Google Scholar). This not and to each to the of a We have used an the which this The approach in to the DNA binding specificity of proteins J.M. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar). The approach is for the sequence of proteins. each in the sequence to complex the in with a given site may be In the a of a binding site J.M. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar). The results that each to complex formation the results for the ETS proteins from bases in the G-G-A flanking the to bases that contribute to high sites that the not are the at the and a at the for binding that G-G-A flanking contribute to ETS have been These between sequences and direct L.A. Amores A. Schilling T.F. Jowett T. Baert J.L. de Launoit Y. Sharrocks A.D. Oncogene. 1998; 17: 93-104Crossref PubMed Scopus (54) Google Scholar, 15Li S.L. Schlegel W. Valente A.J. Clark R.A. J. Biol. Chem. 1999; 274: 32453-32460Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 19Shore P. Sharrocks A.D. Nucleic Acids Res. 1995; 23: 4698-4706Crossref PubMed Scopus (77) Google Scholar, L.A. Yang S.H. A. A. Sharrocks A.D. Oncogene. 1999; PubMed Scopus Google Scholar) and binding between two different ETS proteins McKnight S.L. Genes Dev. PubMed Scopus Google Scholar). have for PU.1 and Fli-1 within specific sequence may also be by of sequences are with the these suggest that a of DNA recognition for ETS proteins is an indirect read-out mechanism in which proteins recognize support to the of indirect read-out for ETS The structures of six ETS complexes, by and ETS proteins recognize their DNA (20Liang H. Mao X. Olejniczak E.T. Nettesheim D.G., Yu, L. Meadows R.P. Thompson C.B. Fesik S.W. Nat. Struct. Biol. 1994; 1: 871-875Crossref PubMed Scopus (101) Google Scholar, 22Werner M.H. Clore M. Fisher C.L. Fisher R.J. Trinh L. Shiloach J. Gronenborn A.M. Cell. 1995; 83: 761-771Abstract Full Text PDF PubMed Scopus (110) Google Scholar, 23Werner M.H. Clore G.M. Fisher C.L. Fisher R.J. Trinh L. Shiloach J. Gronenborn A.M. J. Biomol. NMR. 1997; 10: 317-328Crossref PubMed Scopus (59) Google Scholar, R. Pio F. Ni C.Z. Piccialli G. Klemsz M. McKercher S. Maki R.A. Ely K.R. Nature. 1996; 830: 456-460Crossref Scopus (266) Google Scholar, A.H. Piper D.E. de la Brousse F.C. McKnight S.L. Wolberger C. Science. 1998; 279: 1037-1041Crossref PubMed Scopus (266) Google Scholar, Y. Vaessen B. Johnston K. Marmorstein R. Mol. Cell. 1998; 2: 201-212Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, Y. Vaessen B. Johnston K. Marmorstein R. Nat. Struct. Biol. 2000; 7: 292-297Crossref PubMed Scopus (81) Google Scholar). These have the central G-G-A sequence has direct contacts with highly conserved residues in helix 3 of the ETS the and of these contacts the protein of and Fli-1 that the conserved Arg residues that interact with G-G-A not have a conformation when to DNA (20Liang H. Mao X. Olejniczak E.T. Nettesheim D.G., Yu, L. Meadows R.P. Thompson C.B. Fesik S.W. Nat. Struct. Biol. 1994; 1: 871-875Crossref PubMed Scopus (101) Google Scholar, 23Werner M.H. Clore G.M. Fisher C.L. Fisher R.J. Trinh L. Shiloach J. Gronenborn A.M. J. Biomol. NMR. 1997; 10: 317-328Crossref PubMed Scopus (59) Google Scholar). they to be in between several with the bases flanking the G-G-A by both conserved and residues are few and often by a conserved and protein within the of the direct contacts with phosphates within the minor flanking the G-G-A The pattern and of contacts from protein complex to of these structures and several have been to sequence specificity specific acid interactions. these to the a of the crystal has been that the at is residues to and of SAP-1 (26Mo Y. Vaessen B. Johnston K. Marmorstein R. Mol. Cell. 1998; 2: 201-212Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) Fli-1 and SAP-1 have residues at these yet Fli-1 an at the SAP-1 can also a for the that of SAP-1 recognizes a or an by with the or the for SAP-1 this is by and which suggest that a is also at this site. These direct and between protein residues and DNA bases not for ETS binding The pattern of contacts between ETS domains and the DNA further an indirect read-out mechanism J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus (30) Google Scholar). The of ETS domains the DNA P. 1998; PubMed Scopus Google Scholar) with the contacts along the two minor that the central G-G-A major The at the of the ETS domain the bending of DNA around the protein. from crystal structures between 11 and Because the for DNA to is Scopus Google Scholar), is likely that the between protein and DNA will a specific sequence upstream and downstream of the that may not be by direct between protein and DNA of the sequence of a protein is to of DNA in the that interact with a given protein. from the sequences by an of these the of the bases at each in a to the and The sequence to is which not with or with for ETS protein S. Marais R. Child R. Light Y. Leonard W.J. J. Exp. Med. 1996; 183: 743-750Crossref PubMed Scopus (30) Google Scholar). The between and may from two is possible that high sites are in the the expression of some genes a high of the ETS protein for Because high sites of ETS proteins to be between genes may between lower binding sites in to their tissue specific the proteins residues in the flanking of the G-G-A results in a in The is the in for SAP-1 by the bases at the and in the ETS binding of the and than a in binding with and R.J. G. A. Papas T.S. Oncogene. Google J.A. Petersen J.M. Graves B.J. Genes Dev. PubMed Scopus Google Scholar). major that a in recognition is cooperative protein-protein between ETS proteins and transcription factors at DNA sites (1Sharrocks A.D. Brown A.L. Ling Y. Yates P.R. Int. J. Biochem. Cell Biol. 1997; 29: 1371-1387Crossref PubMed Scopus (279) Google Scholar). ETS proteins identified to date in which can the or specificity of the ETS domain for a DNA site. Thus, is not that sites to not to high sites of ETS proteins. This the of high sites for the other of high ETS sites be for sequences which may be by ETS proteins. The of proteins and their in are is the of as a transcription identified as a transcriptional its not the of the ETS domain C. C. P. J. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). The DNA-binding domain of is to the sequence H. C. C. E. Y. A. M. M. R. J. Oncogene. 1997; PubMed Scopus Google Scholar), specificity have been Our suggests that the sequence of is unique to the other ETS proteins the other proteins, an sequence downstream of the G-G-A other ETS proteins not an at the or a at of the G-G-A has for and at the other ETS proteins a at this We and for and for with

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