Regulation of FOXC1 Stability and Transcriptional Activity by an Epidermal Growth Factor-activated Mitogen-activated Protein Kinase Signaling Cascade

Mutations in the FOXC1 transcription factor gene result in Axenfeld Rieger malformations, a disorder that affects the anterior segment of the eye, the teeth, and craniofacial structures. Individuals with this disorder possess an elevated risk for developing glaucoma. Previous work in our laboratory has indicated that FOXC1 transcriptional activity may be regulated by phosphorylation. We report here that FOXC1 is a short-lived protein (t½<30 min), and serine 272 is a critical residue in maintaining proper stability of FOXC1. Furthermore, we have demonstrated that activation of the ERK1/2 mitogen-activated protein kinase through epidermal growth factor stimulation is required for maximal FOXC1 transcriptional activation and stability. Finally, we have demonstrated that FOXC1 is targeted to the ubiquitin 26 S proteasomal degradation pathway and that amino acid residues 367–553, which include the C-terminal transactivation domain of FOXC1, are essential for ubiquitin incorporation and proteolysis. These results indicate that FOXC1 protein levels and activity are tightly regulated by post-translational modifications. Mutations in the FOXC1 transcription factor gene result in Axenfeld Rieger malformations, a disorder that affects the anterior segment of the eye, the teeth, and craniofacial structures. Individuals with this disorder possess an elevated risk for developing glaucoma. Previous work in our laboratory has indicated that FOXC1 transcriptional activity may be regulated by phosphorylation. We report here that FOXC1 is a short-lived protein (t½<30 min), and serine 272 is a critical residue in maintaining proper stability of FOXC1. Furthermore, we have demonstrated that activation of the ERK1/2 mitogen-activated protein kinase through epidermal growth factor stimulation is required for maximal FOXC1 transcriptional activation and stability. Finally, we have demonstrated that FOXC1 is targeted to the ubiquitin 26 S proteasomal degradation pathway and that amino acid residues 367–553, which include the C-terminal transactivation domain of FOXC1, are essential for ubiquitin incorporation and proteolysis. These results indicate that FOXC1 protein levels and activity are tightly regulated by post-translational modifications. Protein phosphorylation provides a rapid means of altering the function of a protein in response to changes in the cellular environment. In the case of transcription factors, phosphorylation can alter the activity of these proteins through regulation of their nuclear localization (1Nguyen T. Sherratt P.J. Huang H.C. Yang C.S. Pickett C.B. J. Biol. Chem. 2003; 278: 4536-4541Abstract C.S. of their C.S. J. J. Biol. Chem. and by their stability J. Biol. Chem. the phosphorylation of a transcription factor can activity and a an to an transcription factor FOXC1 is an for the proper and function of and T. T. T. J. J. J. T. Biol. In in the FOXC1 gene Axenfeld Rieger malformations, a disorder that is by a of of the anterior segment of the T. T. J. J. J. of this disorder is a to with of developing this In to the can with a of and In targeted of results in and T. T. Biol. T. T. an essential transcription work in our laboratory has demonstrated that the FOXC1 transcription factor is a and that amino acid residues to a in the FOXC1 protein by J. Biol. Chem. of this this and results in a FOXC1 We to the residues that are in FOXC1 and the for the phosphorylation can to the of FOXC1 by in the and to in these to of FOXC1 the J. FOXC1 the to FOXC1. to the of the and in with mitogen-activated protein epidermal growth with J. Biol. Chem. and in a and and activation a J. Biol. Chem. in and by to a and for Biol. FOXC1 with a of and and factor the of FOXC1 of nuclear by and proteins to a FOXC1 to and with the a of and for with FOXC1 to the to for the of the of the for the Protein by and protein by and by and FOXC1 levels to that of ERK1/2 of of FOXC1 in J. Huang Biol. 2003; to amino acid residues the proteins in and by in and of with FOXC1 of and in kinase and for by in and by proteins by and proteins by the incorporation of ubiquitin FOXC1 with of FOXC1 with an by of an in the FOXC1 an to FOXC1. of protein with acid for and with and proteins by in and by and ERK1/2 a FOXC1 is that ERK1/2 activity can growth and and of the FOXC1 are to result T. T. Biol. Biol. 2003; the the 2003; ERK1/2 in FOXC1 residues and These residues to by Furthermore, a that results in a in FOXC1 has in T. T. amino acid to is a this serine residue to an and in our the FOXC1 proteins for activation of a we that and FOXC1 transactivation In the activity of FOXC1, that this residue can FOXC1 transcriptional In we that a in the protein levels of FOXC1 with FOXC1 with that the protein levels of a result of a in the and an in levels of protein that the affects FOXC1 protein levels to the that of We an with FOXC1 and that the levels of FOXC1 and the levels of FOXC1 in with the that the levels of the FOXC1 transactivation and protein we our this the the stability of FOXC1, we the of FOXC1 and with the protein in the levels of FOXC1 with FOXC1, we a of protein with levels of FOXC1 FOXC1 levels with a of levels of with a of that the the stability of FOXC1 by a the affects phosphorylation of FOXC1. We a which for a of FOXC1 J. Biol. Chem. are in with the FOXC1 in These indicate that is is for a FOXC1 phosphorylation for the of the in the that phosphorylation of FOXC1 protein levels of with levels that amino are required for proteolysis. 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Biol. Chem. in this we have demonstrated that the of the residues FOXC1 stability and the of regulation of FOXC1 function by phosphorylation. the FOXC1 protein transcriptional activation by that the protein may be the levels of by the levels of FOXC1 in a activation by that this result in a of function ERK1/2 pathway is in FOXC1 activity and of ERK1/2 activity through means through the of growth can FOXC1 protein These indicate the that FOXC1 protein stability may be regulated the and FOXC1 may in for the of Biol. 2003; T. T. of the in Axenfeld Rieger with FOXC1 in are to an of T. T. Biol. T. Biol. 2003; the ERK1/2 pathway is in growth and J. 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In of our that FOXC1 a is that the by of FOXC1 protein levels through post-translational has for the of FOXC1 in is of in Axenfeld Rieger with FOXC1 is a of in the of In of Axenfeld Rieger with FOXC1 glaucoma. are in the of the in these is that the regulation of FOXC1 activity and through post-translational the activity of FOXC1 protein the which for the In this these glaucoma. the levels of FOXC1 protein the may be through an of the in FOXC1. levels of FOXC1 may the FOXC1 and these be to developing glaucoma. in the levels of FOXC1 may to the in that possess FOXC1 is by and that results in a of the elevated with of has to the of to the and this of growth to and J. the of growth results in of T. the of can be to and factors, is that these may the that FOXC1 protein stability. the levels and activity of FOXC1 in the may levels and may the in a to FOXC1 levels are by Protein phosphorylation provides a rapid means of altering the function of a protein in response to changes in the cellular environment. In the case of transcription factors, phosphorylation can alter the activity of these proteins through regulation of their nuclear localization (1Nguyen T. Sherratt P.J. Huang H.C. Yang C.S. Pickett C.B. J. Biol. Chem. 2003; 278: 4536-4541Abstract C.S. of their C.S. J. J. Biol. Chem. and by their stability J. Biol. Chem. the phosphorylation of a transcription factor can activity and a an to an transcription factor FOXC1 is an for the proper and function of and T. T. T. J. J. J. T. Biol. In in the FOXC1 gene Axenfeld Rieger malformations, a disorder that is by a of of the anterior segment of the T. T. J. J. J. of this disorder is a to with of developing this In to the can with a of and In targeted of results in and T. T. Biol. T. T. an essential transcription Previous work in our laboratory has demonstrated that the FOXC1 transcription factor is a and that amino acid residues to a in the FOXC1 protein by J. Biol. Chem. of this this and results in a FOXC1 We to the residues that are in FOXC1 and the for the phosphorylation can to the of FOXC1 by in the and to in these to of FOXC1 the J. FOXC1 the to FOXC1. to the of the and in with mitogen-activated protein epidermal growth with J. Biol. Chem. and in a and and activation a J. Biol. Chem. in and by to a and for Biol. FOXC1 with a of and and factor the of FOXC1 of nuclear by and proteins to a FOXC1 to and with the a of and for with FOXC1 to the to for the of the of the for the Protein by and protein by and by and FOXC1 levels to that of ERK1/2 of of FOXC1 in J. Huang Biol. 2003; to amino acid residues the proteins in and by in and of with FOXC1 of and in kinase and for by in and by proteins by and proteins by the incorporation of ubiquitin FOXC1 with of FOXC1 with an by of an in the FOXC1 an to FOXC1. of protein with acid for and with and proteins by in and by and of FOXC1 the J. 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T. amino acid to is a this serine residue to an and in our the FOXC1 proteins for activation of a we that and FOXC1 transactivation In the activity of FOXC1, that this residue can FOXC1 transcriptional In we that a in the protein levels of FOXC1 with FOXC1 with that the protein levels of a result of a in the and an in levels of protein that the affects FOXC1 protein levels to the that of We an with FOXC1 and that the levels of FOXC1 and the levels of FOXC1 in with the that the levels of the FOXC1 transactivation and protein we our this the the stability of FOXC1, we the of FOXC1 and with the protein in the levels of FOXC1 with FOXC1, we a of protein with levels of FOXC1 FOXC1 levels with a of levels of with a of that the the stability of FOXC1 by a the affects phosphorylation of FOXC1. We a which for a of FOXC1 J. Biol. Chem. are in with the FOXC1 in These indicate that is is for a FOXC1 phosphorylation for the of the in the that phosphorylation of FOXC1 protein levels of with levels that amino are required for proteolysis. 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T. Biol. Biol. 2003; the the 2003; ERK1/2 in FOXC1 residues and These residues to by Furthermore, a that results in a in FOXC1 has in T. T. amino acid to is a this serine residue to an and in our the FOXC1 proteins for activation of a we that and FOXC1 transactivation In the activity of FOXC1, that this residue can FOXC1 transcriptional In we that a in the protein levels of FOXC1 with FOXC1 with that the protein levels of a result of a in the and an in levels of protein that the affects FOXC1 protein levels to the that of We an with FOXC1 and that the levels of FOXC1 and the levels of FOXC1 in with the that the levels of the FOXC1 transactivation and protein we our this the the stability of FOXC1, we the of FOXC1 and with the protein in the levels of FOXC1 with FOXC1, we a of protein with levels of FOXC1 FOXC1 levels with a of levels of with a of that the the stability of FOXC1 by a We the affects phosphorylation of FOXC1. We a which for a of FOXC1 J. Biol. Chem. are in with the FOXC1 in These indicate that is is for a FOXC1 phosphorylation for the of the in the that phosphorylation of FOXC1 protein levels of with levels that amino are required for proteolysis. We a a protein to residues of FOXC1 and to be a for in kinase with phosphorylation of with FOXC1, that is is for maximal phosphorylation of this in by protein in FOXC1 stability to phosphorylation we the of protein kinase FOXC1 protein with the mitogen-activated protein kinase kinase and FOXC1 protein a for and kinase in the regulation of FOXC1 protein levels with with epidermal growth factor to activation of the pathway affects the levels of FOXC1 indicated in levels of FOXC1 the levels of FOXC1. the of FOXC1 are the of the changes in protein levels are to be the changes in gene are to an protein stability that is we the levels and stability of FOXC1 protein to FOXC1 with and FOXC1 protein levels by indicated in the levels of FOXC1 to of and FOXC1 is of the of FOXC1 to be of the protein with that of the protein the levels of FOXC1 with that of FOXC1. levels of FOXC1 in with with in with that the stability of FOXC1 is regulated by activation of of by stimulation to a of FOXC1 transcriptional activity in with FOXC1 and in with to by in with that this residue is critical for this transcriptional activation of FOXC1 in response to be that growth in FOXC1 transcriptional activity with We ERK1/2 in with ERK1/2 of stimulation These results indicate that to FOXC1 transcriptional activation in response to Finally, we to FOXC1 protein stability to the S with FOXC1 and with the proteasomal and levels of elevated in response to and with with an of the degradation and These that the results in a stability of FOXC1 and degradation is by the 26 S proteasomal the 26 S and proteins with we FOXC1 this ubiquitin with and proteins by with indicated in in with FOXC1 and the with these with FOXC1 that with FOXC1. these indicate that FOXC1 is with in which of FOXC1 are required for of ubiquitin to the we a of FOXC1 in FOXC1 amino of the C-terminal residue These with our that the C-terminal of FOXC1 is essential for proteolysis. this we have demonstrated that FOXC1 is a short-lived transcription factor that is through the ubiquitin 26 S FOXC1 stability and activity is regulated through the ERK1/2 and is of FOXC1 the residues 367–553, which include the C-terminal transactivation is required a for of ubiquitin is required for the of an We that phosphorylation of is in that FOXC1 stability In the FOXC1 is by ERK1/2 residue may to a factor the of an to the of FOXC1. work the that of FOXC1 be essential in our of FOXC1 transcriptional activity and work has indicated that the of residues to a of FOXC1 J. Biol. Chem. in this we have demonstrated that the of the residues FOXC1 stability and the of regulation of FOXC1 function by phosphorylation. the FOXC1 protein transcriptional activation by that the protein may be the levels of by the levels of FOXC1 in a activation by that this result in a of function ERK1/2 pathway is in FOXC1 activity and of ERK1/2 activity through means through the of growth can FOXC1 protein These indicate the that FOXC1 protein stability may be regulated the and FOXC1 may in for the of Biol. 2003; T. T. of the in Axenfeld Rieger with FOXC1 in are to an of T. T. Biol. T. Biol. 2003; the ERK1/2 pathway is in growth and J. Biol. 2003; is that ERK1/2 activity to the regulation of FOXC1 protein stability of a of the transcription factor is regulated by phosphorylation. and and nuclear J. 2003; the phosphorylation of degradation through the 26 S 2003; in phosphorylation of FOXC1 by ERK1/2 the stability of levels of FOXC1 in the be the of function of a is to anterior segment in and in T. T. T. J. J. J. T. Biol. T. of the that the FOXC1 result in a of that include an for developing T. J. in FOXC1 stability may to the Axenfeld Rieger levels of FOXC1 protein the have J. In of our that FOXC1 a is that the by of FOXC1 protein levels through post-translational has for the of FOXC1 in is of in Axenfeld Rieger with FOXC1 is a of in the of In of Axenfeld Rieger with FOXC1 glaucoma. are in the of the in these is that the regulation of FOXC1 activity and through post-translational the activity of FOXC1 protein the which for the In this these glaucoma. the levels of FOXC1 protein the may be through an of the in FOXC1. levels of FOXC1 may the FOXC1 and these be to developing glaucoma. in the levels of FOXC1 may to the in that possess FOXC1 is by and that results in a of the elevated with of has to the of to the and this of growth to and J. the of growth results in of T. the of can be to and factors, is that these may the that FOXC1 protein stability. the levels and activity of FOXC1 in the may levels and may the in a to FOXC1 levels are by In this we have demonstrated that FOXC1 is a short-lived transcription factor that is through the ubiquitin 26 S FOXC1 stability and activity is regulated through the ERK1/2 and is of FOXC1 the residues 367–553, which include the C-terminal transactivation is required a for of ubiquitin is required for the of an We that phosphorylation of is in that FOXC1 stability In the FOXC1 is by ERK1/2 residue may to a factor the of an to the of FOXC1. work the that of FOXC1 be essential in our of FOXC1 transcriptional activity and work has indicated that the of residues to a of FOXC1 J. Biol. Chem. in this we have demonstrated that the of the residues FOXC1 stability and the of regulation of FOXC1 function by phosphorylation. the FOXC1 protein transcriptional activation by that the protein may be the levels of by the levels of FOXC1 in a activation by that this result in a of function ERK1/2 pathway is in FOXC1 activity and of ERK1/2 activity through means through the of growth can FOXC1 protein These indicate the that FOXC1 protein stability may be regulated the and FOXC1 may in for the of Biol. 2003; T. T. of the in Axenfeld Rieger with FOXC1 in are to an of T. T. Biol. T. Biol. 2003; the ERK1/2 pathway is in growth and J. Biol. 2003; is that ERK1/2 activity to the regulation of FOXC1 protein stability of a of the transcription factor is regulated by phosphorylation. and and nuclear J. 2003; the phosphorylation of degradation through the 26 S 2003; in phosphorylation of FOXC1 by ERK1/2 the stability of FOXC1. levels of FOXC1 in the be the of function of a is to anterior segment in and in T. T. T. J. J. J. T. Biol. T. of the that the FOXC1 result in a of that include an for developing T. J. in FOXC1 stability may to the Axenfeld Rieger levels of FOXC1 protein the have J. In of our that FOXC1 a is that the by FOXC1. of FOXC1 protein levels through post-translational has for the of FOXC1 in is of in Axenfeld Rieger with FOXC1 is a of in the of In of Axenfeld Rieger with FOXC1 glaucoma. are in the of the in these is that the regulation of FOXC1 activity and through post-translational the activity of FOXC1 protein the which for the In this these glaucoma. the levels of FOXC1 protein the may be through an of the in FOXC1. levels of FOXC1 may the FOXC1 and these be to developing glaucoma. in the levels of FOXC1 may to the in that possess FOXC1 is by and that results in a of the elevated with of has to the of to the and this of growth to and J. the of growth results in of T. the of can be to and factors, is that these may the that FOXC1 protein stability. the levels and activity of FOXC1 in the may levels and may the in a to FOXC1 levels are by We for We of for the In we and of the the of for the

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