Phosphorylation of Histones by Tissue Transglutaminase

Tissue transglutaminase 2 (TG2) has recently been shown to have intrinsic serine/threonine kinase activity. Since histones are known to be cross-linked by TG2, we investigated whether histones are also substrates for TG2 kinase activity. TG2 was able to phosphorylate H1, H2A, H2B, H3, and H4 histones in vitro. Using peptide substrates and phosphospecific antibodies we demonstrated that TG2 phosphorylated Ser10 in H3 and that this phosphorylation was reduced by acetylation, whereas phosphorylation of Ser10 by TG2 enhanced acetylation. Furthermore we demonstrated that exogenous TG2 phosphorylated H1 and H3 in nucleosome preparations. We examined the abundance of TG2 in DNA-associated proteins from MCF-7 cells treated with phorbol ester (TPA) and 17β-estradiol (E2). TG2 abundance was significantly reduced in E2-treated cells and enhanced in TPA-treated cells. In summary we have demonstrated that TG2 is able to phosphorylate purified histone proteins, and H3 and H1 in chromatin preparations, and it is associated with chromatin in breast cancer cells. These studies suggest a novel role for TG2 in the regulation of chromatin structure and function. Tissue transglutaminase 2 (TG2) has recently been shown to have intrinsic serine/threonine kinase activity. Since histones are known to be cross-linked by TG2, we investigated whether histones are also substrates for TG2 kinase activity. TG2 was able to phosphorylate H1, H2A, H2B, H3, and H4 histones in vitro. Using peptide substrates and phosphospecific antibodies we demonstrated that TG2 phosphorylated Ser10 in H3 and that this phosphorylation was reduced by acetylation, whereas phosphorylation of Ser10 by TG2 enhanced acetylation. Furthermore we demonstrated that exogenous TG2 phosphorylated H1 and H3 in nucleosome preparations. We examined the abundance of TG2 in DNA-associated proteins from MCF-7 cells treated with phorbol ester (TPA) and 17β-estradiol (E2). TG2 abundance was significantly reduced in E2-treated cells and enhanced in TPA-treated cells. In summary we have demonstrated that TG2 is able to phosphorylate purified histone proteins, and H3 and H1 in chromatin preparations, and it is associated with chromatin in breast cancer cells. These studies suggest a novel role for TG2 in the regulation of chromatin structure and function. Tissue transglutaminase 2 (TG2) 4The abbreviations used are: TG2, tissue transglutaminase 2; TPA, phorbol ester; E2, 17β-estradiol; HAT, histone acetyltransferase; HRP, horseradish peroxidase; DMEM, Dulbecco’s modified Eagle’s medium. 4The abbreviations used are: TG2, tissue transglutaminase 2; TPA, phorbol ester; E2, 17β-estradiol; HAT, histone acetyltransferase; HRP, horseradish peroxidase; DMEM, Dulbecco’s modified Eagle’s medium. is a ubiquitously expressed, calcium-dependent trans-amidating acyltransferase that cross-links proteins resulting in polymerization (1Fesus L. Piacentini M. Trends Biochem. Sci. 2002; 27: 534-539Abstract Full Full In it has a M. M. Biochem. a and a serine/threonine kinase Full Full is to in the the the and the (1Fesus L. Piacentini M. Trends Biochem. Sci. 2002; 27: 534-539Abstract Full Full TG2 is in a of of the is it is for the of is to the by a that M. it histones M. L. Full Full of the histone and H2B, by TG2 to and M. Biochem. H1, has also been shown to be a for TG2 M. Biochem. in a to to are to that to be in chromatin function. the of histones be phosphorylated and and are to chromatin structure to and by TG2 be for the in and the have been and it that TG2 histones from the Since of histone by TG2 the histones in nucleosome M. Biochem. it is this of TG2 have recently demonstrated that TG2, in to to proteins, also has intrinsic kinase Full Full H2A, H2B, H3, and and histone H1 are known to be and it has been that phosphorylation of for H3 by and Biochem. in histone phosphorylation have also been of the M. TG2 is by a of that M. and TG2 cells are to L. TG2 also Full Full Biochem. has been that it is the TG2 that is in are that this of TG2 be to of TG2, the Full Full In this we investigated whether histones are substrates for TG2 kinase and cells from the Tissue from TG2, in was from from from histone proteins from with of TG2 in kinase and for the of phosphorylation was and the of the phosphorylation histone and of to the and for in a was by of for and and for In proteins to and by phosphorylated proteins and and with to phosphorylated proteins and and the in a was of the of of of histones with in for the of of TG2 and with to the and for was by of and the for and by and for to and by of the proteins, treated with the of proteins and and the was in a proteins and to in and with the antibodies for of phosphorylation of a with phosphospecific antibodies in and with horseradish antibodies for of the histone in with for with from cells in with histone 2 with of in of for the of in of in to and for 2 with for and the in for in of and by by and was Full Full and a for of TG2 with and MCF-7 breast cells in with and in a with was cells and in and to the of the in treated with for with for and chromatin was chromatin are in histones and in the kinase from MCF-7 by Full Full the phosphorylation of by TG2 in H3 in the of was in and in of the of from MCF-7 cells with of the for the of the the was by was and for phosphorylation in the of and proteins to the and for of DNA-associated by cells MCF-7 cells with for with the of in cells and in 2 2 and was to chromatin and associated proteins, and the was was with of with the proteins cross-linked to for and histones and H1 phosphorylated by TG2 in and was phosphorylated by TG2 and of and the the of was in the with the peptide that of the the and In the was with the histone that the of the of histone was in the histone was phosphorylated by TG2, whereas the peptide was of the phosphorylation of H4 in the In the of TG2 of the histone that the of the was to TG2 and a of a kinase and the histone was phosphorylated was that TG2 phosphorylated in the H3 of the H3 in the of the histone and is also shown in peptide was whereas the peptide the of of peptide and the the was with TG2 and of the peptide was of the the of for the to be with to the of histones and histone of in in in in in in a H3 In of and with TG2 and and by and of was of of the peptide was In the was with to of phosphorylation in H3, we H3 that phosphorylation is to be was phosphorylated by TG2 H3 was used a phosphorylation of was with phosphospecific H3 Ser10 and of H3 and phosphorylated by TG2 in the of and by and by and of of of the histone TG2 phosphorylation was TG2 phosphorylation of the and reduced the and We examined the of phosphorylation of the histone and the In of was with the peptide phosphorylation enhanced of the peptide by the of the 4The of and In phosphorylation of and and H3 was In of the with TG2 in the of to with and In the with to in a and has been in of TG2 phosphorylation of histone and of of of phosphorylation of in a TG2 H3 in chromatin from with TG2 in kinase histone a and by histone and a to and by and histone H2A, H2B, and H4 phosphorylated histone H3 was of was also histone H1 In the of TG2 histone phosphorylation was that the phosphorylation of H3 and H1 was to the TG2 and to a kinase in the nucleosome H1 and H3 in In with TG2 and histones a and of the is In with in the of TG2 a for kinase activity. These a in H3 phosphorylated in the nucleosome we the nucleosome to with Ser10 and phosphospecific antibodies Ser10 and in H3 in from MCF-7 and treated with to phosphorylation to with TG2 and by and with histone used to the of TG2 with that of TG2 with H2A, H2B, H3, and H4 In this H3 peptide was the H4 peptide was the was the was with that and in the with H3 and H4 was with to histone In from cells was with the a the by and with was with TG2 is the a in a In a for of TG2 with proteins, was to cells and and with in MCF-7 associated proteins from and and TPA-treated MCF-7 cells by the and by and with abundance in TG2 abundance was significantly reduced in E2-treated cells and enhanced in TPA-treated cells of TG2 in DNA-associated proteins from MCF-7 cells. DNA-associated proteins from MCF-7 cells treated with the of TG2 and H3 by In the from by we that TG2 has intrinsic kinase Full Full and that known substrates for the of TG2 Full Full M. Biochem. are also substrates for TG2 kinase activity. We have shown that the and for the TG2 kinase are with Full Full and are to in TG2 is in cells and is kinase is to it be by Full Full kinase is also with TG2 and the kinase with TG2 in in kinase in TG2 was able to phosphorylate and this phosphorylation Ser10 and in H3 and in the of we that TG2 is able to phosphorylate H3 and H1 in nucleosome of the phosphorylation of H3 a that has been shown to be in of and for and Trends Full Full have been that have the to phosphorylate H3 Ser10 in Sci. and suggest that TG2 in this in vitro. and in H3 to be in to phosphorylation Ser10 in Trends Full Full Sci. with we demonstrated that of the peptide in reduced phosphorylation whereas phosphorylation of the peptide enhanced acetylation. phosphorylation of H3 has also been shown to be in the regulation of peptide to be a for TG2 kinase in of it was to of the this of TG2 in the has been in M. Biochem. Full Full Full Full M. Full Full In the TG2 to a of is in histone and chromatin L. Piacentini M. is also in and have a In TG2 of a of Full Full and and of a of has been a to the of TG2 to known activity. and demonstrated that purified TG2 the of to the by and the of the suggest that this was to the of TG2 to this was and is that TG2 the phosphorylation that has been shown to be in is to of the of TG2 are in the that TG2 has been the TG2 have been Full Full L. Piacentini M. Full Full it has been whether also TG2 kinase TG2 is by by Full Full M. Biochem. are also to also of TG2 activity. of of TG2 are this also TG2 kinase Full Full of TG2 to be by and Full Full L. L. L. Piacentini M. Full Full of TG2 whereas the to be We have that TG2 kinase is by and enhanced by Full Full whereas the of TG2 is and by (1Fesus L. Piacentini M. Trends Biochem. Sci. 2002; 27: 534-539Abstract Full Full the for the of TG2 to be by the with of of TG2 to the Full Full we that TG2 phosphorylate H3 and to a H1 in chromatin and that TG2 is associated with chromatin in in breast cancer cells. We also demonstrated in that TG2 has for histone of TG2 with chromatin was reduced by E2, a known to in MCF-7 and enhanced by TPA, summary we have demonstrated that TG2 is able to phosphorylate histones and is associated with chromatin in cells. it the of TG2 kinase histone phosphorylation in of the of TG2 of of to be in of TG2 kinase activity. with TG2 that are to the of TG2 and of this Tissue transglutaminase 2 (TG2) 4The abbreviations used are: TG2, tissue transglutaminase 2; TPA, phorbol ester; E2, 17β-estradiol; HAT, histone acetyltransferase; HRP, horseradish peroxidase; DMEM, Dulbecco’s modified Eagle’s medium. 4The abbreviations used are: TG2, tissue transglutaminase 2; TPA, phorbol ester; E2, 17β-estradiol; HAT, histone acetyltransferase; HRP, horseradish peroxidase; DMEM, Dulbecco’s modified Eagle’s medium. is a ubiquitously expressed, calcium-dependent trans-amidating acyltransferase that cross-links proteins resulting in polymerization (1Fesus L. Piacentini M. Trends Biochem. Sci. 2002; 27: 534-539Abstract Full Full In it has a M. M. Biochem. a and a serine/threonine kinase Full Full is to in the the the and the (1Fesus L. Piacentini M. Trends Biochem. Sci. 2002; 27: 534-539Abstract Full Full TG2 is in a of of the is it is for the of TG2 is to the by a that M. it histones M. L. Full Full of the histone and H2B, by TG2 to and M. Biochem. H1, has also been shown to be a for TG2 M. Biochem. in a to to are to that to be in chromatin function. the of histones be phosphorylated and and are to chromatin structure to and by TG2 be for the in and the have been and it that TG2 histones from the Since of histone by TG2 the histones in nucleosome M. Biochem. it is this of TG2 We have recently demonstrated that TG2, in to to proteins, also has intrinsic kinase Full Full H2A, H2B, H3, and and histone H1 are known to be and it has been that phosphorylation of for H3 by and Biochem. in histone phosphorylation have also been of the M. TG2 is by a of that M. and TG2 cells are to L. TG2 also Full Full Biochem. has been that it is the TG2 that is in are that this of TG2 be to of TG2, the Full Full In this we investigated whether histones are substrates for TG2 kinase activity. and cells from the Tissue from TG2, in was from from from histone proteins from with of TG2 in kinase and for the of phosphorylation was and the of the phosphorylation histone and of to the and for in a was by of for and and for In proteins to and by phosphorylated proteins and and with to phosphorylated proteins and and the in a was of the of of of histones with in for the of of TG2 and with to the and for was by of and the for and by and for to and by of the proteins, treated with the of proteins and and the was in a proteins and to in and with the antibodies for of phosphorylation of a with phosphospecific antibodies in and with horseradish antibodies for of the histone in with for with from cells in with histone 2 with of in of for the of in of in to and for 2 with for and the in for in of and by by and was Full Full and a for of TG2 with and MCF-7 breast cells in with and in a with was cells and in and to the of the in treated with for with for and chromatin was chromatin are in histones and in the kinase from MCF-7 by Full Full the phosphorylation of by TG2 in H3 in the of was in and in of the of from MCF-7 cells with of the for the of the the was by was and for phosphorylation in the of and proteins to the and for of DNA-associated by cells MCF-7 cells with for with the of in cells and in 2 2 and was to chromatin and associated proteins, and the was was with of with the proteins cross-linked to for and and cells from the Tissue from TG2, in was from from from In histone proteins from with of TG2 in kinase and for the of phosphorylation was and the of the phosphorylation histone and of to the and for in a was by of for and and for In proteins to and by phosphorylated proteins and and with to phosphorylated proteins and and the in a was of In the of of of histones with in for the of of TG2 and with to the and for was by of and the for and by and for to and by of the proteins, treated with the of proteins and and the was in a proteins and to in and with the antibodies for of phosphorylation of a with phosphospecific antibodies in and with horseradish antibodies for of the histone in with for with from cells in with histone 2 with of in of for the of in of in to and for 2 with for and the in for in of and by by and was Full Full and a for of TG2 with and MCF-7 breast cells in with and in a with was cells and in and to the of the in treated with for with for and chromatin was chromatin are in histones and in the kinase from MCF-7 by Full Full the phosphorylation of by TG2 in H3 in the of was in and in of the of from MCF-7 cells with of the for the of the the was by was and for phosphorylation in the of and proteins to the and for of DNA-associated by cells MCF-7 cells with for with the of in cells and in 2 2 and was to chromatin and associated proteins, and the was was with of with the proteins cross-linked to for and histones and H1 phosphorylated by TG2 in and was phosphorylated by TG2 and of and the the of was in the with the peptide that of the the and In the was with the histone that the of the of histone was in the histone was phosphorylated by TG2, whereas the peptide was of the phosphorylation of H4 in the In the of TG2 of the histone that the of the was to TG2 and a of a kinase and the histone was phosphorylated was that TG2 phosphorylated in the H3 of the H3 in the of the histone and is also shown in peptide was whereas the peptide the of of peptide and the the was with TG2 and of the peptide was of the the of for the to be with to the of histones and histone of in in in in in in a of phosphorylation in H3, we H3 that phosphorylation is to be was phosphorylated by TG2 H3 was used a phosphorylation of was with phosphospecific H3 Ser10 and of H3 and phosphorylated by TG2 in the of and by and by and of of of the histone TG2 phosphorylation was TG2 phosphorylation of the and reduced the and We examined the of phosphorylation of the histone and the In of was with the peptide phosphorylation enhanced of the peptide by the of the 4The of and In phosphorylation of and and H3 was In of the with TG2 in the of to with and In the with to in a and has been in of TG2 phosphorylation of histone and of of of phosphorylation of in a TG2 H3 in chromatin from with TG2 in kinase histone a and by histone and a to and by and histone H2A, H2B, and H4 phosphorylated histone H3 was of was also histone H1 In the of TG2 histone phosphorylation was that the phosphorylation of H3 and H1 was to the TG2 and to a kinase in the nucleosome H1 and H3 in In with TG2 and histones a and of the is In with in the of TG2 a for kinase activity. These a in H3 phosphorylated in the nucleosome we the nucleosome to with Ser10 and phosphospecific antibodies Ser10 and in H3 in from MCF-7 and treated with to phosphorylation to with TG2 and by and with histone used to the of TG2 with that of TG2 with H2A, H2B, H3, and H4 In this H3 peptide was the H4 peptide was the was the was with that and in the with H3 and H4 was with to histone In from cells was with the a the by and with was with TG2 is the a in a In a for of TG2 with proteins, was to cells and and with in MCF-7 associated proteins from and and TPA-treated MCF-7 cells by the and by and with abundance in TG2 abundance was significantly reduced in E2-treated cells and enhanced in TPA-treated cells of TG2 in DNA-associated proteins from MCF-7 cells. DNA-associated proteins from MCF-7 cells treated with the of TG2 and H3 by In the from by TG2 histones and H1 phosphorylated by TG2 in and was phosphorylated by TG2 and of and the the of was in the with the peptide that of the the and In the was with the histone that the of the of histone was in the histone was phosphorylated by TG2, whereas the peptide was of the phosphorylation of H4 in the In the of TG2 of the histone that the of the was to TG2 and a of a kinase and the histone was phosphorylated was that TG2 phosphorylated in the H3 of the H3 in the of the histone and is also shown in peptide was whereas the peptide the of of peptide and the the was with TG2 and of the peptide was of the the of for the to be with to the of phosphorylation in H3, we H3 that phosphorylation is to be was phosphorylated by TG2 H3 was used a phosphorylation of was with phosphospecific of of of the histone TG2 phosphorylation was TG2 phosphorylation of the and reduced the and We examined the of phosphorylation of the histone and the In of was with the peptide phosphorylation enhanced of the peptide by the of the TG2 H3 in chromatin from with TG2 in kinase histone a and by histone and a to and by and histone H2A, H2B, and H4 phosphorylated histone H3 was of was also histone H1 In the of TG2 histone phosphorylation was that the phosphorylation of H3 and H1 was to the TG2 and to a kinase in the nucleosome in H3 phosphorylated in the nucleosome we the nucleosome to with Ser10 and phosphospecific antibodies TG2 with histone used to the of TG2 with that of TG2 with H2A, H2B, H3, and H4 In this H3 peptide was the H4 peptide was the was the was with that and in the with H3 and H4 was with TG2 with in MCF-7 associated proteins from and and TPA-treated MCF-7 cells by the and by and with abundance in TG2 abundance was significantly reduced in E2-treated cells and enhanced in TPA-treated cells we that TG2 has intrinsic kinase Full Full and that known substrates for the of TG2 Full Full M. Biochem. are also substrates for TG2 kinase activity. We have shown that the and for the TG2 kinase are with Full Full and are to in TG2 is in cells and is kinase is to it be by Full Full kinase is also with TG2 and the kinase with TG2 in in kinase in TG2 was able to phosphorylate and this phosphorylation Ser10 and in H3 and in the of we that TG2 is able to phosphorylate H3 and H1 in nucleosome of the phosphorylation of H3 a that has been shown to be in of and for and Trends Full Full have been that have the to phosphorylate H3 Ser10 in Sci. and suggest that TG2 in this in vitro. and in H3 to be in to phosphorylation Ser10 in Trends Full Full Sci. with we demonstrated that of the peptide in reduced phosphorylation whereas phosphorylation of the peptide enhanced acetylation. phosphorylation of H3 has also been shown to be in the regulation of peptide to be a for TG2 kinase in of it was to of the this of TG2 in the has been in M. Biochem. Full Full Full Full M. Full Full In the TG2 to a of is in histone and chromatin L. Piacentini M. is also in and have a In TG2 of a of Full Full and and of a of has been a to the of TG2 to known activity. and demonstrated that purified TG2 the of to the by and the of the suggest that this was to the of TG2 to this was and is that TG2 the phosphorylation that has been shown to be in is to of the of TG2 are in the that TG2 has been the TG2 have been Full Full L. Piacentini M. Full Full it has been whether also TG2 kinase TG2 is by by Full Full M. Biochem. are also to also of TG2 activity. of of TG2 are this also TG2 kinase Full Full of TG2 to be by and Full Full L. L. L. Piacentini M. Full Full of TG2 whereas the to be We have that TG2 kinase is by and enhanced by Full Full whereas the of TG2 is and by (1Fesus L. Piacentini M. Trends Biochem. Sci. 2002; 27: 534-539Abstract Full Full the for the of TG2 to be by the with of of TG2 to the Full Full we that TG2 phosphorylate H3 and to a H1 in chromatin and that TG2 is associated with chromatin in in breast cancer cells. We also demonstrated in that TG2 has for histone of TG2 with chromatin was reduced by E2, a known to in MCF-7 and enhanced by TPA, summary we have demonstrated that TG2 is able to phosphorylate histones and is associated with chromatin in cells. it the of TG2 kinase histone phosphorylation in of the of TG2 of of to be in of TG2 kinase activity. with TG2 that are to the of TG2 and of this we that TG2 has intrinsic kinase Full Full and that known substrates for the of TG2 Full Full M. Biochem. are also substrates for TG2 kinase activity. We have shown that the and for the TG2 kinase are with Full Full and are to in TG2 is in cells and is kinase is to it be by Full Full kinase is also with TG2 and the kinase with TG2 in in kinase in TG2 was able to phosphorylate and this phosphorylation Ser10 and in H3 and in the of we that TG2 is able to phosphorylate H3 and H1 in nucleosome preparations. of the phosphorylation of H3 a that has been shown to be in of and for and Trends Full Full have been that have the to phosphorylate H3 Ser10 in Sci. and suggest that TG2 in this in vitro. and in H3 to be in to phosphorylation Ser10 in Trends Full Full Sci. with we demonstrated that of the peptide in reduced phosphorylation whereas phosphorylation of the peptide enhanced acetylation. phosphorylation of H3 has also been shown to be in the regulation of peptide to be a for TG2 kinase in of it was to of the this of TG2 in the has been in M. Biochem. Full Full Full Full M. Full Full In the TG2 to a of is in histone and chromatin L. Piacentini M. is also in and have a In TG2 of a of Full Full and and of a of has been a to the of TG2 to known activity. and demonstrated that purified TG2 the of to the by and the of the suggest that this was to the of TG2 to this was and is that TG2 the phosphorylation that has been shown to be in is to of the of TG2 are in the that TG2 has been the TG2 have been Full Full L. Piacentini M. Full Full it has been whether also TG2 kinase TG2 is by by Full Full M. Biochem. are also to also of TG2 activity. of of TG2 are this also TG2 kinase Full Full of TG2 to be by and Full Full L. L. L. Piacentini M. Full Full of TG2 whereas the to be We have that TG2 kinase is by and enhanced by Full Full whereas the of TG2 is and by (1Fesus L. Piacentini M. Trends Biochem. Sci. 2002; 27: 534-539Abstract Full Full the for the of TG2 to be by the with of of TG2 to the Full Full we that TG2 phosphorylate H3 and to a H1 in chromatin and that TG2 is associated with chromatin in in breast cancer cells. We also demonstrated in that TG2 has for histone of TG2 with chromatin was reduced by E2, a known to in MCF-7 and enhanced by TPA, In summary we have demonstrated that TG2 is able to phosphorylate histones and is associated with chromatin in cells. it the of TG2 kinase histone phosphorylation in of the of TG2 of of to be in of TG2 kinase activity. with TG2 that are to the of TG2 and of this We for the

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