SUMO Modification of the Ets-related Transcription Factor ERM Inhibits Its Transcriptional Activity

A variety of transcription factors are post-translationally modified by SUMO, a 97-residue ubiquitin-like protein bound covalently to the targeted lysine. Here we describe SUMO modification of the Ets family member ERM at positions 89, 263, 293, and 350. To investigate how SUMO modification affects the function of ERM, Ets-responsive intercellular adhesion molecule 1 (ICAM-1) and E74 reporter plasmids were employed to demonstrate that SUMO modification causes inhibition of ERM-dependent transcription without affecting the subcellular localization, stability, or DNA-binding capacity of the protein. When the adenoviral protein Gam1 or the SUMO protease SENP1 was used to inhibit the SUMO modification pathway, ERM-dependent transcription was de-repressed. These results demonstrate that ERM is subject to SUMO modification and that this post-translational modification causes inhibition of transcription-enhancing activity. A variety of transcription factors are post-translationally modified by SUMO, a 97-residue ubiquitin-like protein bound covalently to the targeted lysine. Here we describe SUMO modification of the Ets family member ERM at positions 89, 263, 293, and 350. To investigate how SUMO modification affects the function of ERM, Ets-responsive intercellular adhesion molecule 1 (ICAM-1) and E74 reporter plasmids were employed to demonstrate that SUMO modification causes inhibition of ERM-dependent transcription without affecting the subcellular localization, stability, or DNA-binding capacity of the protein. When the adenoviral protein Gam1 or the SUMO protease SENP1 was used to inhibit the SUMO modification pathway, ERM-dependent transcription was de-repressed. These results demonstrate that ERM is subject to SUMO modification and that this post-translational modification causes inhibition of transcription-enhancing activity. Covalent modification of proteins with ubiquitin-like proteins creates new proteins with unique protein surfaces that can mediate a range of protein-protein interactions (reviewed in Ref. 1Seeler J.S. Dejean A. Nat. Rev. Mol. Cell. Biol. 2003; 4: 690-699Crossref PubMed Scopus (581) Google Scholar). Modification of proteins by the small ubiquitin-related modifier (SUMO) is increasingly recognized as an important regulatory mechanism that can affect the stability, subnuclear localization, and transcription-activating capacity of the protein (reviewed in Refs. 1Seeler J.S. Dejean A. Nat. Rev. Mol. Cell. Biol. 2003; 4: 690-699Crossref PubMed Scopus (581) Google Scholar and 2Girdwood D.W. Tatham M.H. Hay R.T. Semin. Cell Dev. Biol. 2004; 15: 201-210Crossref PubMed Scopus (152) Google Scholar). Several transcription factors are reported to undergo SUMO modification, including the androgen receptor (3Poukka H. Karvonen U. Janne O.A. Palvimo J.J. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 14145-14150Crossref PubMed Scopus (371) Google Scholar, 4Callewaert L. Verrijdt G. Haelens A. Claessens F. Mol. Endocrinol. 2004; 18: 1438-1449Crossref PubMed Scopus (59) Google Scholar), c-Myb (5Bies J. Markus J. Wolff L. J. Biol. Chem. 2002; 277: 8999-9009Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar), AP-2 (6Eloranta J.J. Hurst H.C. J. Biol. Chem. 2002; 277: 30798-30804Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar), and c-Jun and p53 (7Muller S. Berger M. Lehembre F. Seeler J.S. Haupt Y. Dejean A. J. Biol. Chem. 2000; 275: 13321-13329Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar). In addition, other transcriptional regulators, such as GRIP (8Kotaja N. Karvonen U. Janne O.A. Palvimo J.J. J. Biol. Chem. 2002; 277: 30283-30288Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar) and histone deacetylases 1 (9David G. Neptune M.A. DePinho R.A. J. Biol. 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Three different types of enzyme constitute the SUMO pathway: ubiquitin-activating enzyme (E1), 1The abbreviations used are: E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; E3, ubiquitin-protein isopeptide ligase; EMSA, electrophoretic mobility shift assay; MAPK, mitogen-activated protein kinase; ICAM, intercellular adhesion molecule; KR12345, K89R,K263R,K293R,K350R,K468R; EA12345, E89A,E263A,E293A, E350A,E468A; CPB, CREB-binding protein; CREB, cAMP-response element-binding protein. ubiquitin-conjugating enzyme or carrier protein (E2), and ubiquitin-protein isopeptide ligase (E3). Although Ubc9 is the only E2 (conjugating enzyme) found in humans, multiple E3 ligases have recently been identified. SUMO modification is a reversible process, and several SUMO proteases have been identified in mammalian cells (reviewed in Ref. 1Seeler J.S. Dejean A. Nat. Rev. Mol. Cell. Biol. 2003; 4: 690-699Crossref PubMed Scopus (581) Google Scholar). In mammals, the ets genes encode a large family of transcription factors, characterized by their ETS DNA-binding domain. On the basis of conservation of this and other domains, these factors have been subclassified into 13 groups (for a review, see Ref. 11Sharrocks A.D. Nat. Rev. Mol. Cell. Biol. 2001; 2: 827-837Crossref PubMed Scopus (827) Google Scholar). Some Ets transcription factors have been identified as targets of SUMO. For instance, Elk-1 is modified by SUMO, a modification that is reversed by signaling via the prototype extracellular signal-regulated kinase (ERK) MAPK pathway, which induces a switch from the repressed to the transcriptionally active state (12Yang S.H. Jaffray E. Hay R.T. Sharrocks A.D. Mol. Cell. 2003; 12: 63-74Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 13Yang S.H. Jaffray E. Senthinathan B. Hay R.T. Sharrocks A.D. Cell Cycle. 2003; 2: 528-530Crossref PubMed Scopus (35) Google Scholar). SUMO modification of Elk-1 results in the recruitment of histone deacetylase activity to promoters; this indicates the existence of an important integration point for two protein-modifying pathways in the cell, the SUMO and deacetylation pathways, which combine to promote inhibition of transcription-enhancing activity (14Yang S.H. Sharrocks A.D. Mol. Cell. 2004; 13: 611-617Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). SUMO has also been shown to enhance the recruitment of the Ets transcription factor Tel into repressive domains such as the PML bodies (15Chakrabarti S.R. Nucifora G. Biochem. Biophys. Res. Commun. 1999; 264: 871-877Crossref PubMed Scopus (120) Google Scholar, 16Chakrabarti S.R. Sood R. Nandi S. Nucifora G. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 13281-13285Crossref PubMed Scopus (100) Google Scholar, 17Wood L.D. Irvin B.J. Nucifora G. Luce K.S. Hiebert S.W. Proc. Natl. Acad. Sci. U. S. 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This suggests that these factors may contribute to the nuclear response to cell stimulation and also to Ras-induced transformation (25Janknecht R. Monte D. Baert J.L. de Launoit Y. Oncogene. 1996; 13: 1745-1754PubMed Google Scholar, 26O'Hagan R.C. Tozer R.G. Symons M. McCormick F. Hassell J.A. Oncogene. 1996; 13: 1323-1333PubMed Google Scholar, 27O'Hagan R.C. Hassell J.A. Oncogene. 1998; 16: 301-310Crossref PubMed Scopus (65) Google Scholar, 28Bosc D.G. Goueli B.S. Janknecht R. Oncogene. 2001; 20: 6215-6224Crossref PubMed Scopus (97) Google Scholar, 29Bosc D.G. Janknecht R. J. Cell. Biochem. 2002; 86: 174-183Crossref PubMed Scopus (38) Google Scholar, 30Janknecht R. Oncogene. 2003; 22: 746-755Crossref PubMed Scopus (86) Google Scholar). The c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) and cAMP-dependent protein kinase (PKA) pathways are also involved in regulating the transcription-enhancing activity of the PEA3 group members R. Oncogene. 2003; 22: 746-755Crossref PubMed Scopus (86) Google Scholar, J. Janknecht R. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, J.L. Beaudoin C. Coutte L. de Launoit Y. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). In the we have ERM SUMO show that of the SUMO modification of this the can be to SUMO. the results of showing that this post-translational modification can inhibit ERM transcription-enhancing activity. was with the as by the A of ERM was by and with the DNA-binding domain in the at the The was a transformation into the of mammary in the was into the the The were at in the of and A of were for the capacity to in the of and for activity by the were from the and in from the were into were to for plasmids the The were by and and the have been J.L. Beaudoin C. Coutte L. de Launoit Y. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The ERM was the ERM and the used Albagli O. Baert J.L. F. D. de Launoit Y. Oncogene. 1996; 12: Google Scholar) are The ERM to and to were with a and by and plasmids have been M.H. Jaffray E. O.A. J.H. Hay R.T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). reporter we used the (25Janknecht R. Monte D. Baert J.L. de Launoit Y. Oncogene. 1996; 13: 1745-1754PubMed Google Scholar) and the to the human to at positions and Launoit Y. M. H. S. Baert J.L. Oncogene. 1998; 16: PubMed Scopus Google Scholar). The was used to J.L. Beaudoin C. Coutte L. de Launoit Y. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). SENP1 and were by E. T. H. of M. D. Anderson J. D. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar) and the Gam1 and were a from S. of Cell and and human cells were in modified with and at in or were in and the were the of including of reporter of and of When of the plasmids the or molecule were activity was and with to the activity as a of the as Launoit Y. M. H. S. Baert J.L. Oncogene. 1998; 16: PubMed Scopus Google Scholar). The are of at three To of ERM, or cells were with of ERM with of or cells were with and in or For the of protein cells were with ERM and plasmids for and with the cells were for and with ERM were with for and in and protease the of of and the was at for at 4 The was with at 4 the proteins were with and by were used as in were to were with the (22Baert J.L. Monte D. Musgrove E.A. Albagli O. Sutherland R.L. de Launoit Y. Int. J. Cancer. 1997; 70: 590-597Crossref PubMed Scopus (88) Google Scholar) or with the or by with were by to of cells were in were by as M. D. Cell. Full Text PDF PubMed Scopus Google Scholar). cells in were in and in of The were at for at 4 was with of and at The were with three with and with in and by were to and were by a as In SUMO Modification for SUMO modification were by in in germ to the In modification was with as M.H. Jaffray E. O.A. J.H. Hay R.T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). were by and by was and in as A of the was with 1 of the E74 in the of 1 1 and 1 of The was for 1 at and a The was at 4 in at J.L. Beaudoin C. Coutte L. de Launoit Y. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). cells were with the different ERM the cells were in for at and for with This was by for 1 with SUMO Modification of we a human mammary in the a of the ERM molecule as were found to encode the human were used to for ERM to Ubc9 Ubc9 as a protein. Ubc9 is the enzyme J. Hay R.T. 1997; PubMed Scopus Google Scholar) and ERM large M.S. C. Hay R.T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google we to ERM is a in and in To show that ERM is a SUMO modification ERM was by in and with components for SUMO modification M.H. Jaffray E. O.A. J.H. Hay R.T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). in of the indicates that a large of the ERM was by or to in a the enzyme and the E2 enzyme To that ERM is modified by SUMO in we cells with plasmids for ERM and or were SUMO modification, and ERM proteins were identified by with an In the of SUMO, we a protein to were only or was these the of multiple high suggests that multiple SUMO modifications in were other cell such as the also in the of SUMO and were in the of To that these to of ERM, cells with ERM and were and proteins were proteins were and by with ERM was and the ERM were in the that ERM is modified by SUMO at multiple in and in SUMO Modification of the for modification by SUMO To of SUMO modification the ERM we of ERM and their to be in by with in Although ERM was modified by SUMO at multiple was modified at only and to be These that and are targets of SUMO modification, with or is that in a the is a of SUMO To the of SUMO modification, we or in with an to as a SUMO cells were with a for or ERM with the ERM was by that the of has ERM SUMO A of or the of at ERM and a was for the When and were in the of ERM were the was of the SUMO modification of in with the of the to This modified was and were and was with ERM at at of the SUMO modification of ERM in These that SUMO modification only at and of the identified in ERM, the in the of ERM is the only that is in ERM in to in cell such as or SUMO H. J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), we the of SUMO to ERM in of cells to For this cells were with plasmids for or and cells were or with The cell were to with and the were by with ERM or SUMO. the ERM was In ERM were in the These ERM were with the their was the of the To which of SUMO was to ERM, from cells with the were by an or an The of ERM were with the with the These were ERM was This indicates that are for ERM in SUMO in ERM with of investigate the of SUMO modification ERM transcription-enhancing we the of and of the protein to ERM-dependent reporter In with the human Ets-responsive Launoit Y. M. H. S. Baert J.L. Oncogene. 1998; 16: PubMed Scopus Google Scholar), the ERM an increase in transactivation ERM at of the the or the transactivation as ERM ERM proteins and an transactivation increase was with the and ERM The reporter used three E74 from the kinase Although ERM with the E74 the E74 reporter without stimulation by post-translational modification such as phosphorylation J.L. Beaudoin C. Coutte L. de Launoit Y. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). shown in cells with the E74 reporter and a the or a ERM activity. When a ERM was transactivation to and by the and the ERM in the in a of ERM was by of these results show that the ERM has an transcriptional capacity and that is to in in the transcriptional activity of the ERM is to of protein as reported for other proteins X. M. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, M.S. Hay R.T. Mol. Cell. 1998; 2: Full Text Full Text PDF PubMed Scopus Google Scholar). the of and ERM inhibition of protein cells with ERM were from to with the protein and by In to which is by ERM is with a of this is also found in the ERM were also in cells with ERM and to the of the of in the as with ERM or the ERM These results that of the of ERM affects ERM also the DNA-binding capacity of the ERM from that of protein. with nuclear of cells ERM or KR12345, we that the was by the of the shown that in only a small of the ERM protein is and the of ERM DNA-binding capacity was to in these To we ERM by in to in SUMO modification and DNA-binding these ERM was and shift with an E74 recognized by ERM J.L. Beaudoin C. Coutte L. de Launoit Y. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) a mobility of were for the and the and This indicates that in transcriptional activity and ERM is of DNA-binding a by have shown that SUMO modification of ERM affect the subcellular localization, the protein stability, and the DNA-binding activity of ERM, of the the SUMO transcriptional in to the can be modified by a number of post-translational modifications including and To that transcriptional activity of ERM at of the is to SUMO modification, we the activity of the protein by the of to without the of the are reported to SUMO by affecting the of the with the enzyme Ubc9 V. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In the transcription of ERM at was to that of the ERM in the and E74 reporter results were also in the ERM the ERM be modified by SUMO, in to ERM that the of SUMO modification with transcriptional activation of The that the transcriptional activity of the In reporter we used two proteins to with the SUMO pathway: the adenoviral protein which the SUMO pathway by the of and R. R. Hay R.T. S. Mol. Cell. 2004; 16: Full Text Full Text PDF PubMed Scopus Google and a protease involved in J. D. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). protein transcription from the and E74 reporter plasmids In the E74 reporter Gam1 and SENP1 a increase in the activity of This increase was the of the Gam1 SENP1 the transcriptional activity of the ERM In reporter the results were proteins transactivation by ERM, and activity in the of these the of ERM transactivation capacity was to the of these two proteins to with the SUMO pathway, as the transcriptional activity of ERM was only by of of Gam1 and SENP1 These demonstrate that the transcriptional activity of ERM is by the SUMO ERM transcription-enhancing activity is by post-translational modifications such as phosphorylation via the MAPK and cAMP-dependent protein kinase pathways (25Janknecht R. Monte D. Baert J.L. de Launoit Y. Oncogene. 1996; 13: 1745-1754PubMed Google Scholar, J.L. Beaudoin C. Coutte L. de Launoit Y. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). Here we show that ERM with the enzyme Ubc9 and is modified by SUMO. show that SUMO modification of this Ets transcription factor affects to have that of the in M.S. C. Hay R.T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google the ERM and are modified by SUMO in and in When the or the of these are SUMO modification of the ERM These SUMO are in and ERM This suggests that SUMO modification of the ERM transcription factor an important role in These are also in the two other PEA3 group and have that of these also undergo in SUMO modification On the the which is modified in ERM, is in ERM, human or mouse In these three the of this is by an ERM can be modified by SUMO at multiple and multiple of ERM are in Although to with ERM, the SUMO modification for ERM in cells are for and M.H. Jaffray E. O.A. J.H. Hay R.T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). is that the of ERM at multiple SUMO modification at a also The modified protein be the ERM this ERM is the only three of the SUMO are The of this modified ERM as ERM is and is Although this is for and is to an of the modified of and and to protein targets has been have that can with proteins via to the mechanism of and has been that the and the other show different H. J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. A. M. J. Biol. Chem. 2003; Scholar). When three SUMO have the capacity to to ERM, in ERM was in cells with only the of was This is in with the that the of into in response to H. J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). this a modification by to be SUMO modification has been reported for several and of their function the as transcription factors or transcriptional or (for review, see Ref. 1Seeler J.S. Dejean A. Nat. Rev. Mol. Cell. Biol. 2003; 4: 690-699Crossref PubMed Scopus (581) Google Scholar). we show that the Ets transcription ERM, is to SUMO modification and that this post-translational modification affects transcription-activating SUMO ERM proteins a capacity to two to SUMO modification by and ERM transcriptional they only a of the transcriptional activity. these for an important role of SUMO modification ERM transcriptional activity. A SUMO modification and inhibition of activity has been for other transcription factors such as and c-Myb (for review, see Ref. 1Seeler J.S. Dejean A. Nat. Rev. Mol. Cell. Biol. 2003; 4: 690-699Crossref PubMed Scopus (581) Google Scholar). of these proteins SUMO ERM, which has of This high number of SUMO may be for that SUMO modification of is to the transcriptional activity of Although of a increase the of ERM the of three of the and is to the transcriptional ERM is at This only to the the E74 ERM a transcription-enhancing ERM This suggests that to the the repressive of may in function of the number and of reported for other such as the Ets protein Elk-1 S.H. Jaffray E. Senthinathan B. Hay R.T. Sharrocks A.D. Cell Cycle. 2003; 2: 528-530Crossref PubMed Scopus (35) Google Scholar), only a small of ERM protein is of the ERM or inhibition of the has a the ERM transcription-enhancing activity. This is SUMO modification is a and this modification, to transcriptional is to this The mechanism to SUMO inhibition of transcription-enhancing activity is we show that this inhibition is to in the or DNA-binding activity of be that be to SUMO SUMO an repressive to the of J.S. Dejean A. Nat. Rev. Mol. Cell. Biol. 2003; 4: 690-699Crossref PubMed Scopus (581) Google Scholar). a repressive mechanism histone deacetylase as for D. D. O.A. A. Anderson E. Hay R.T. Mol. Cell. 2003; 11: Full Text Full Text PDF PubMed Scopus Google Scholar) and Elk-1 (14Yang S.H. Sharrocks A.D. Mol. Cell. 2004; 13: 611-617Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). that SUMO with the recruitment of by ERM by the with transcriptional for transcriptional activity. In transcriptional activity of ERM be by which is a of the PEA3 group members A. Janknecht R. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar) and a of SUMO the recruitment of by ERM, the ERM transcriptional and ERM activity be by the of activity by recruitment of D. D. O.A. A. Anderson E. Hay R.T. Mol. Cell. 2003; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). has been shown that SUMO targets proteins to different in nuclear ERM and SUMO we the that SUMO modification of ERM the in a currently into nuclear domains or affect the nuclear of this transcription as shown for the Ets proteins Tel and Elk-1 L.D. Irvin B.J. Nucifora G. Luce K.S. Hiebert S.W. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 3257-3262Crossref PubMed Scopus (100) Google Scholar, S. A. G. M.A. M. I. A. R.A. J. Cell Biol. 2004; PubMed Scopus Google Scholar). are to the by which SUMO the activity of are to for

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