Transcriptional regulation of catecholamine-synthesizing genes is important for the determination of neurotransmitters during brain development. We found that three catecholamine-synthesizing genes were transcriptionally up-regulated in cloned PC12D cells overexpressing V-1, a protein that is highly expressed during postnatal brain development (1Yamakuni T. Yamamoto T. Hoshino M. Song S.Y. Yamamoto H. Kunikata-Sumitomo M. Minegishi A. Kubota M. Ito M. Konishi S. J. Biol. Chem. 1998; 273: 27051-27054Google Scholar). To reveal the molecular mechanism to regulate the expression of tyrosine hydroxylase (TH), which is the rate-limiting enzyme for catecholamine biosynthesis, we analyzed the transcription factors responsible for TH induction in the V-1 clonal cells. First, by using reporter constructs, we found that the transcription mediated by cAMP-responsive element (CRE) was selectively enhanced in the V-1 cells, and TH promoter activity was totally dependent on the CRE in the promoter region of the TH gene. Next, immunoblot analyses and a transactivation assay using a GAL4 reporter system revealed that ATF-2, but not cAMP-responsive element-binding protein (CREB), was highly phosphorylated and activated in the V-1 cells, while both CREB and ATF-2 were bound to the TH-CRE. Finally, the enhanced TH promoter activity was competitively attenuated by expression of a plasmid containing the ATF-2 transactivation domain. These data demonstrated that activation of ATF-2 resulted in the increased transcription of the TH gene and suggest that ATF-2 may be deeply involved in the transcriptional regulation of catecholamine-synthesizing genes during neural development. Transcriptional regulation of catecholamine-synthesizing genes is important for the determination of neurotransmitters during brain development. We found that three catecholamine-synthesizing genes were transcriptionally up-regulated in cloned PC12D cells overexpressing V-1, a protein that is highly expressed during postnatal brain development (1Yamakuni T. Yamamoto T. Hoshino M. Song S.Y. Yamamoto H. Kunikata-Sumitomo M. Minegishi A. Kubota M. Ito M. Konishi S. J. Biol. Chem. 1998; 273: 27051-27054Google Scholar). To reveal the molecular mechanism to regulate the expression of tyrosine hydroxylase (TH), which is the rate-limiting enzyme for catecholamine biosynthesis, we analyzed the transcription factors responsible for TH induction in the V-1 clonal cells. First, by using reporter constructs, we found that the transcription mediated by cAMP-responsive element (CRE) was selectively enhanced in the V-1 cells, and TH promoter activity was totally dependent on the CRE in the promoter region of the TH gene. Next, immunoblot analyses and a transactivation assay using a GAL4 reporter system revealed that ATF-2, but not cAMP-responsive element-binding protein (CREB), was highly phosphorylated and activated in the V-1 cells, while both CREB and ATF-2 were bound to the TH-CRE. Finally, the enhanced TH promoter activity was competitively attenuated by expression of a plasmid containing the ATF-2 transactivation domain. These data demonstrated that activation of ATF-2 resulted in the increased transcription of the TH gene and suggest that ATF-2 may be deeply involved in the transcriptional regulation of catecholamine-synthesizing genes during neural development. Catecholamines are synthesized from l-tyrosine by the sequential action of four enzymes: tyrosine is converted to DOPA by tyrosine hydroxylase (TH), 1The abbreviations used are: TH, tyrosine hydroxylase; AADC, aromatic l-amino acid decarboxylase; DBH, dopamine β-hydroxylase; CRE, cAMP-responsive element; CREB, cAMP-responsive element-binding protein; CREM, cAMP-responsive element modulator; PKA, protein kinase A; FSK, forskolin; NGF, nerve growth factor; GCH, GTP cyclohydrolase I; MEKK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase. 1The abbreviations used are: TH, tyrosine hydroxylase; AADC, aromatic l-amino acid decarboxylase; DBH, dopamine β-hydroxylase; CRE, cAMP-responsive element; CREB, cAMP-responsive element-binding protein; CREM, cAMP-responsive element modulator; PKA, protein kinase A; FSK, forskolin; NGF, nerve growth factor; GCH, GTP cyclohydrolase I; MEKK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase. DOPA to dopamine by aromatic l-amino acid decarboxylase (AADC), dopamine to norepinephrine by dopamine β-hydroxylase (DBH), and norepinephrine to epinephrine by phenylethanolamineN-methyltransferase. The regulation of the gene expression of these enzymes is important for the determination of the expression of neurotransmitters during brain development as well as for brain function under physiological and pathological conditions. TH is the rate-limiting enzyme for catecholamine biosynthesis. The transcriptional regulation of the TH gene has been extensively studied, and many transcription factors were suggested to regulate TH gene expression. CREB, ATF-1, and CREM were shown to recognize the cAMP-responsive element (CRE) located at position −45/−38 in the TH promoter (2Tinti C. Conti B. Cubells J.F. Kim K.S. Baker H. Joh T.H. J. Biol. Chem. 1996; 271: 25375-25381Google Scholar, 3Kim K.S. Lee M.K. Carroll J. Joh T.H. J. Biol. Chem. 1993; 268: 15689-15695Google Scholar, 4Hyman S.E. Comb M. Lin Y.S. Pearlberg J. Green M.R. Goodman H.M. Mol. Cell. Biol. 1988; 8: 4225-4233Google Scholar, 5Shimomura A. Okamoto Y. Hirata Y. Kobayashi M. Kawakami K. Kiuchi K. Wakabayashi T. Hagiwara M. J. Neurochem. 1998; 70: 1029-1034Google Scholar, 6Usukura J. Nishizawa Y. Shimomura A. Kobayashi K. Nagatsu T. Hagiwara M. Genes Cells. 2000; 5: 515-522Google Scholar). CREB was reported to mediate basal and cAMP-induced TH transcription in various cultured cells including PC12 cells by the use of dominant-negative CREB protein and antisense RNA against CREB (7Swanson D.J. Zellmer E. Lewis E.J. J. Biol. Chem. 1997; 272: 27382-27392Google Scholar, 8Nagamoto-Combs K. Piech K.M. Best J.A. Sun B. Tank A.W. J. Biol. Chem. 1997; 272: 6051-6058Google Scholar, 9Piech-Dumas K.M. Tank A.W. Brain Res. Mol. Brain Res. 1999; 70: 219-230Google Scholar, 10Lazaroff M. Patankar S. Yoon S.O. Chikaraishi D.M. J. Biol. Chem. 1995; 270: 21579-21589Google Scholar). CREB is activated by phosphorylation on Ser133(11Gonzalez G.A. Montminy M.R. Cell. 1989; 59: 675-680Google Scholar, 12Sheng M. McFadden G. Greenberg M.E. Neuron. 1990; 4: 571-582Google Scholar). The activation of CREB by phosphorylation has been shown to mediate PKA-dependent (7Swanson D.J. Zellmer E. Lewis E.J. J. Biol. Chem. 1997; 272: 27382-27392Google Scholar, 13Beitner-Johnson D. Millhorn D.E. J. Biol. Chem. 1998; 273: 19834-19839Google Scholar, 14Nankova B. Hiremagalur B. Menezes A. Zeman R. Sabban E. Brain Res. Mol. Brain Res. 1996; 35: 164-172Google Scholar, 15Lane-Ladd S.B. Pineda J. Boundy V.A. Pfeuffer T. Krupinski J. Aghajanian G.K. Nestler E.J. J. Neurosci. 1997; 17: 7890-7901Google Scholar) and -independent (13Beitner-Johnson D. Millhorn D.E. J. Biol. Chem. 1998; 273: 19834-19839Google Scholar, 14Nankova B. Hiremagalur B. Menezes A. Zeman R. Sabban E. Brain Res. Mol. Brain Res. 1996; 35: 164-172Google Scholar) induction of TH transcription. Functional and physiological roles of ATF-1 and CREM for TH transcription remained unclear. AP-1 transcription factors bound to the TPA-responsive element located at −205/−199 in the TH promoter, which also plays a critical role in the transcriptional induction of the TH gene (16Trocmé C. Mallet J. Biguet N.F. J. Neurosci. Res. 1997; 48: 489-498Google Scholar). Expression of AP-1 family was induced by several stimuli to enhance TH gene transcription, and overexpression of Fra-2 and c-Fos stimulated TH transcription in PC12 and PC18 cells, respectively (17Sun B. Tank A.W. J. Neurochem. 2002; 80: 295-306Google Scholar, 18Nankova B.B. Rivkin M. Kelz M. Nestler E.J. Sabban E.L. J. Neurosci. 2000; 20: 5647-5653Google Scholar). Nurr1 and Ptx3/Pitx3, which are expressed in midbrain dopaminergic neuron at embryonic stage, were recently shown to regulate TH gene expression. Nurr1-null mice lacked TH immunoreactivity in midbrain (19Zetterström R.H. Solomin L. Jansson L. Hoffer B.J. Olson L. Perlmann T. Science. 1997; 276: 248-250Google Scholar), and overexpression of Nurr1 was shown to induce the TH gene expression in neural stem cells (20Sakurada K. Ohshima-Sakurada M. Palmer T.D. Gage F.H. Development (Camb.). 1999; 126: 4017-4026Google Scholar, 21Wagner J. Åkerud P. Castro D.S. Holm P.C. Canals J.M. Snyder E.Y. Perlmann T. Arenas E. Nat. Biotechnol. 1999; 17: 653-659Google Scholar). However, it is unclear whether or not Nurr1 directly acts on its responsive element in the TH promoter region (20Sakurada K. Ohshima-Sakurada M. Palmer T.D. Gage F.H. Development (Camb.). 1999; 126: 4017-4026Google Scholar, 21Wagner J. Åkerud P. Castro D.S. Holm P.C. Canals J.M. Snyder E.Y. Perlmann T. Arenas E. Nat. Biotechnol. 1999; 17: 653-659Google Scholar). Overepxression of Ptx3/Pitx3 activated the TH promoter activity in neuroblastoma cells through its responsive elements (22Cazorla P. Smidt M.P. O'Malley K.L. Burbach J.P. J. Neurochem. 2000; 74: 1829-1837Google Scholar, 23Lebel M. Gauthier Y. Moreau A. Drouin J. J. Neurochem. 2001; 77: 558-567Google Scholar). Three of the catecholamine-synthesizing enzymes, i.e. TH, AADC, and DBH, were up-regulated in cloned PC12D cells overexpressing V-1 (1Yamakuni T. Yamamoto T. Hoshino M. Song S.Y. Yamamoto H. Kunikata-Sumitomo M. Minegishi A. Kubota M. Ito M. Konishi S. J. Biol. Chem. 1998; 273: 27051-27054Google Scholar). V-1 is an adaptor-like protein, the expression of which is transiently high during postnatal brain development (24Taoka M. Yamakuni T. Song S.Y. Yamakawa Y. Seta K. Okuyama T. Isobe T. Eur. J. Biochem. 1992; 207: 615-620Google Scholar, 25Taoka M. Isobe T. Okuyama T. Watanabe M. Kondo H. Yamakawa Y. Ozawa F. Hishinuma F. Kubota M. Minegishi A. Song S.-Y. Yamakuni T. J. Biol. Chem. 1994; 269: 9946-9951Google Scholar). Therefore, V-1 potentially participate TH gene expression in postnatal brain development. We were interested in the intracellular events in the V-1-overexpressing PC12D cells, because none of the transcription factors are known to induce these catecholamine-synthesizing genes simultaneously. In the present study, we found that the transcription mediated by CRE was specifically and highly elevated in the V-1 cells, and that transcription of the TH gene is enhanced by activation of ATF-2, which directly acted on the CRE in the TH promoter. Our suggest that ATF-2 is involved in the expression of the TH gene during neural development. PC12D and highly V-1, and and and were as (1Yamakuni T. Yamamoto T. Hoshino M. Song S.Y. Yamamoto H. Kunikata-Sumitomo M. Minegishi A. Kubota M. Ito M. Konishi S. J. Biol. Chem. 1998; 273: 27051-27054Google Scholar). PC12D cells were cultured in containing and The were cultured in containing TH containing of its and was from a and cloned the plasmid First, to which the region of from the transcriptional to the of the TH we a containing of the TH region by using and and The region from the transcriptional position and the was to a reporter The of the TH region was by using an Next, to a that to the region and from the transcriptional position was by the of and of To a CRE of that a in a CRE of the TH promoter region we the to in a plasmid in the of the CRE the and reporter containing a or element of a promoter region from kinase promoter were from The were from as of and are to and expression and are expression that of CREB and ATF-2 transactivation to the GAL4 is the for and reporter is a reporter plasmid containing of the and were used as an to for in were by using to the cells were on and at In the shown in the cells were of the reporter and of In using the GAL4 system shown in cells were of of or and of a of a or a was used for of the PC12D cells, and plasmid was used as a In the shown in the cells were of or promoter of or and of the cells were and for and by using a assay of transcription in the V-1 reporter a or element and from the promoter region from the kinase and to The the responsive element and has The activity of the reporter gene in was as activation to the activity of the in the was using are the from three to of for CRE of V-1 were from the and the are assay using a TH promoter of a reporter plasmid containing of the TH region reporter activity of in V-1-overexpressing and and and was was used as an to for in are the from three were from the and the are of a protein in the V-1 expression for and of the transactivation of CREB and ATF-2 and the of the GAL4 The reporter GAL4 the reporter in the of and were in the V-1 and and in the PC12D cells. was used as an to for in a or a was used for of the PC12D cells. are the from in of were on the of the PC12D activity of the TH promoter in the V-1 was attenuated by expression of ATF-2 transactivation domain. of the TH promoter and promoter were The reporter were used for the expression for or a for and was used as an to for in The and the PC12D cells were are the from in of were on the of the were three in and in a at for of for and immunoblot of phosphorylated the was and were as Res. Scholar) that of a for and of and of the was by the of Biochem. Scholar), used as a of for immunoblot of phosphorylated the was directly in and the was as the The were at in and antisense of were and by use of kinase. were as by B.B. Rivkin M. Kelz M. Nestler E.J. Sabban E.L. J. Neurosci. 2000; 20: 5647-5653Google Scholar) a the of and of or were on for to the of the and the was by the of the The was for at was as by G. K. J. Biol. Chem. 2000; Scholar), and was by the for at and against CREB, ATF-2, and were from were the The was by and to a were was used for of was as We that TH protein and were elevated in V-1-overexpressing and for the and (1Yamakuni T. Yamamoto T. Hoshino M. Song S.Y. Yamamoto H. Kunikata-Sumitomo M. Minegishi A. Kubota M. Ito M. Konishi S. J. Biol. Chem. 1998; 273: 27051-27054Google Scholar). To the transcription of the TH gene in the V-1 and we the cloned cells plasmid containing of TH region to a reporter gene activity to was increased in the V-1 that in the that the increased of TH in the V-1 was to an increased transcriptional and that elements located the of region of the TH gene were for the overexpression of the TH gene. To the transcriptional events in the V-1 we promoter of reporter genes containing and In the V-1 we found that the transcriptional activity mediated by CRE was elevated that in the that mediated by the elements was CRE in the region of the TH gene E.J. Chikaraishi D.M. S. A. Scholar), and the and its the are highly and C. C. H. Conti B. Kim C. Joh T.H. Kim K.S. J. Biol. Chem. 1997; 272: Scholar). was shown that the was for both basal and transcription of the TH gene in various including PC12 cells K.S. Lee M.K. Carroll J. Joh T.H. J. Biol. Chem. 1993; 268: 15689-15695Google Scholar, M. Baker H. Brain Res. Mol. Brain Res. 1998; Scholar) and a of PC12 E.J. Chikaraishi D.M. S. A. Scholar). To the of the increased activity of transcription to the increased transcription of the TH gene in the V-1 clonal cells, we and TH reporter containing of the TH region from the transcriptional The reporter activity of the was increased in cells as been the for The reporter activity of the CRE was the as that of the in and the PC12D cells for the V-1 were to for not These the of the transcription for the regulation of the TH gene expression in the V-1 cells. To transcriptional factors that be involved in the transcription of the TH we an assay using of PC12D cells and analyzed that a the were that in a by the of of However, an of also the of to the as the and remained that and the to the TH-CRE. to and an to that and containing ATF-2 and CREB, ATF-2 was reported to to CRE as a or as a F. Green M.R. Genes 1989; Scholar, T. T. S. A. Scholar, T. H. C. T. T. J. M. S. J. 1989; 8: Scholar), we whether was in the not containing ATF-2 We also an assay using and of V-1 and was in V-1 or and the PC12D cells not These data suggest that to the including CREB and ATF-2, were not in the V-1 CREB and ATF-2 are well phosphorylation of CREB on G.A. Montminy M.R. Cell. 1989; 59: 675-680Google Scholar, 12Sheng M. McFadden G. Greenberg M.E. Neuron. 1990; 4: 571-582Google Scholar) or phosphorylation of ATF-2 on C. G. J. 1995; Scholar, S. D. B. Science. 1995; Scholar) the transcription. we CREB and ATF-2 as transcription factors to the as was shown in we the phosphorylation and expression of CREB and ATF-2 in the V-1 by using phosphorylated and against CREB or PC12D cells were or nerve growth for G.A. Montminy M.R. Cell. 1989; 59: 675-680Google Scholar, A. Greenberg M.E. Cell. 1994; 77: Scholar). In of or PC12D cells, the of CREB was increased that were the against CREB phosphorylated on and the of was by and that CREB was its In phosphorylation of ATF-2 was also increased by or in PC12D cells, while the of ATF-2 protein was In the V-1 were or in the expression and phosphorylation of CREB in the and the PC12D cells the of the phosphorylated of ATF-2 was increased in the expression of ATF-2 of and ATF-2 that the phosphorylated of the protein and is the transcriptionally C. G. J. 1995; Scholar, S. D. B. Science. 1995; Scholar). of ATF-2 was increased in of the V-1 that in of the the the of ATF-2 was not increased in the of the V-1 We also used the GAL4 reporter assay to expression the transactivation of CREB or ATF-2 or to a the activity in the PC12D cells transiently a expression was activity in the V-1 was that in the and the PC12D cells In the activity in the V-1 was increased and was that in PC12D cells transiently an expression as a These data ATF-2, as a protein, was highly phosphorylated and activated in the V-1 To whether the enhanced activity of the TH gene transcription was to activation of ATF-2, we the expression to the reporter assay for the TH promoter. of the protein containing the phosphorylation was to competitively the activation of the ATF-2 protein for the TH gene transcription. The reporter activity of in the was by the expression that the that expressed was used for that in the PC12D cells was but not The increased TH promoter activity in the V-1 remained by the expression in to the expression In to the TH promoter, the promoter was not activated in the V-1 and not by the expression of or In the present study, we found that transcription was highly elevated in V-1-overexpressing of the PC12D We ATF-2 as of the in PC12D cells, for the found that activation of ATF-2 up-regulated the TH gene transcription ATF-2 F. Green M.R. Genes 1989; Scholar), also T. H. C. T. T. J. M. S. J. 1989; 8: Scholar), is a of the family of transcription factors that to The was shown to be by of the CREB, ATF-1, and CREM (2Tinti C. Conti B. Cubells J.F. Kim K.S. Baker H. Joh T.H. J. Biol. Chem. 1996; 271: 25375-25381Google Scholar, 3Kim K.S. Lee M.K. Carroll J. Joh T.H. J. Biol. Chem. 1993; 268: 15689-15695Google Scholar, 4Hyman S.E. Comb M. Lin Y.S. Pearlberg J. Green M.R. Goodman H.M. Mol. Cell. Biol. 1988; 8: 4225-4233Google Scholar, 5Shimomura A. Okamoto Y. Hirata Y. Kobayashi M. Kawakami K. Kiuchi K. Wakabayashi T. Hagiwara M. J. Neurochem. 1998; 70: 1029-1034Google Scholar, 6Usukura J. Nishizawa Y. Shimomura A. Kobayashi K. Nagatsu T. Hagiwara M. Genes Cells. 2000; 5: 515-522Google Scholar). these transcription CREB was shown to be an of the TH gene transcription (7Swanson D.J. Zellmer E. Lewis E.J. J. Biol. Chem. 1997; 272: 27382-27392Google Scholar, 8Nagamoto-Combs K. Piech K.M. Best J.A. Sun B. Tank A.W. J. Biol. Chem. 1997; 272: 6051-6058Google Scholar, 9Piech-Dumas K.M. Tank A.W. Brain Res. Mol. Brain Res. 1999; 70: 219-230Google Scholar, 10Lazaroff M. Patankar S. Yoon S.O. Chikaraishi D.M. J. Biol. Chem. 1995; 270: 21579-21589Google Scholar). Our data that CREB is of the in PC12D cells However, data that the enhanced transcription of the TH gene in the V-1 was by a because CREB phosphorylation was In to CREB, we that ATF-2 was highly phosphorylated on and in the V-1 and that activity was enhanced was the V-1 and cells in expression of ATF-2 by immunoblot and in of ATF-2 to the by the assay not the protein containing the phosphorylation a dominant-negative for the enhanced activity of the TH promoter in the V-1 cells data that phosphorylation of ATF-2 induced the TH gene transcription in the V-1 The as kinase S. D. B. Science. 1995; Scholar) and J. S. M. J. J. Biol. Chem. 1995; 270: Scholar), both of which ATF-2, been as of ATF-2 C. G. J. 1995; Scholar, S. D. B. Science. 1995; Scholar, H. D. A. P. P. J. 1995; Scholar). the phosphorylation or expression of these in the V-1 was that of the or PC12D cells, as by against phosphorylated or not we not the kinase that ATF-2 in the V-1 a of these may to the ATF-2 activation in the V-1 is a that the activity of ATF-2, which not been may be in the V-1 is of that the mechanism of the increased phosphorylation of ATF-2 in the V-1 be Our suggest the of phosphorylated ATF-2 in the enhanced transcription in the V-1 are of transcription by phosphorylation of ATF-2 on and Y. J. S. R. T. S. J. Biol. Chem. 1999; Scholar, H. L. R. K. K. Y. 2000; Scholar), the mechanism is In the of CREB, it is well known that phosphorylation of CREB on directly a transcriptional G.A. P. J. Montminy M.R. Cell. 1990; Scholar, Hagiwara M. Montminy M.R. Goodman R.H. 1993; Scholar, D. M. T. A. A. Montminy M. Mol. Cell. Biol. 1999; Scholar), and in the transcriptional activation of the gene. The transactivation of ATF-2, was reported not to phosphorylation Y. F. P. T. Yamamoto T. S. J. Biol. Chem. 1998; 273: Scholar). protein has been as that specifically to phosphorylated ATF-2 to transcription. The V-1 cells be a to the ATF-2 was reported to not to CRE, but also to AP-1 T. T. S. A. Scholar). of L. J. Neurosci. 1998; Scholar) found that ATF-2 bound to a from the the cells been stimulated to induce TH expression. containing ATF-2 was in the of a to a a data of ATF-2 the However, data suggest that the not to the enhanced expression of the TH gene by the activated ATF-2 in the V-1 because the activity of the transcription was in the V-1 NGF, a that of the in the expression of TH E. Genes 1990; 4: Scholar), the transcription in PC12 cells. was reported that of the TH promoter activity was by of the but not by that of the M. Baker H. Brain Res. Mol. Brain Res. 1998; Scholar), enhanced activity of the TH promoter the was by of the K.S. Lee M.K. Carroll J. Joh T.H. J. Biol. Chem. 1993; 268: 15689-15695Google M. Baker H. Brain Res. Mol. Brain Res. 1998; Scholar). The of the promoter activity in the in the V-1 also that transcription is of the of the TH gene transcription in the V-1 of ATF-2 and of T. F. M. S. M. Y. T. H. M. A. S. J. Biol. Chem. 1999; Scholar). In the an increased of TH was shown in the embryonic and the it to in the mice T. F. M. S. M. Y. T. H. M. A. S. J. Biol. Chem. 1999; Scholar). Our may suggest that it a of the of ATF-2 for the TH gene expression. ATF-2 was reported to be for postnatal neural development B. R. S. T. 1996; Scholar), activation of ATF-2 was also in cells, i.e. activation of ATF-2 the of PC12 cells S. M. R. D. Mol. Cell. Biol. 2001; Scholar). may be of ATF-2 to regulate both and of neural cells. the TH gene expression was induced by ATF-2 activation in the V-1 these cells be a for the function of ATF-2 during neural development. GTP cyclohydrolase is the rate-limiting enzyme for the of which is an important of TH activity and the protein C. F. R. T. M. M. H. Y. Nagatsu T. T. H. J. Biol. Chem. 2001; 276: Scholar). In the V-1 clonal cells, we recently an increased and enhanced expression of T. H. Yamakuni T. Nagatsu T. H. Biochem. Res. 2002; Scholar). In study, we increased promoter activity of the gene in the V-1 T. H. Yamakuni T. Nagatsu T. H. Biochem. Res. 2002; Scholar) as we for that of the TH gene in of the region of the gene was as the region to basal and transcriptional activity and containing a CRE G. K. J. Biol. Chem. 2000; Scholar, K. M. L. A. G. J. Neurochem. 2001; Scholar), and we that region was for the increased activity of the promoter in the V-1 T. H. Yamakuni T. Nagatsu T. H. Biochem. Res. 2002; Scholar). K. M. L. A. G. J. Neurochem. 2001; Scholar) reported that the promoter region These suggest that ATF-2 may regulate the expression of both TH and is that the of and were also up-regulated in the V-1 (1Yamakuni T. Yamamoto T. Hoshino M. Song S.Y. Yamamoto H. Kunikata-Sumitomo M. Minegishi A. Kubota M. Ito M. Konishi S. J. Biol. Chem. 1998; 273: 27051-27054Google Scholar), in to of TH and the gene has a CRE in its region to mediate H. Kim Joh T.H. Kim K.S. J. Biol. Chem. 1993; 268: it is that the increased activity of the transcription in the V-1 is responsible for the increased expression of the gene. However, the to the elevated expression of the the it and the transcription has not been the expression of enzyme be by transcription be to roles during neural development. The present data suggest that ATF-2 may be involved in expression of the catecholamine-synthesizing enzymes for the development of In to of the enhanced expression of the catecholamine-synthesizing enzymes in the of PC12D cells overexpressing V-1, of PC12D cells V-1 not enhance the of the and TH genes not an increased expression of TH was in mice overexpressing V-1, T. H. S.-Y. T. K. M. A. R. S. A. Y. C. M. and Y. data suggest that the enhanced expression of the TH gene may be a of expression of we not the action of V-1 in the cells, we that ATF-2 in the V-1 cells were activated and that activation of ATF-2 TH gene transcription. We are the role of ATF-2 in transcription of the TH gene as well as that of catecholamine-synthesizing We and for We also and for
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