Growth/Cell Cycle Regulation of Sp1 Phosphorylation

Sp1 sites can mediate growth/cell cycle induction of dihydrofolate reductase in late G1 (Jensen, D. E., Black, A. R. Swick, A. G., and Azizkhan, J. C. (1997) J. Cell. Biochem. 67, 24–31). To investigate mechanisms underlying this induction, effects of serum stimulation on regulation of Sp1 were examined. In Balb/c 3T3 cells, serum stimulation did not affect Sp1 synthesis or the relative binding of Sp1 family members to DNA; however, it did result in a rapid, ∼2-fold increase in Sp1 levels and an ∼3-fold increase in specific Sp1 phosphorylation in mid-G1. In normal human diploid fibroblasts, serum stimulation also increased Sp1 phosphorylation in mid-G1 but did not affect Sp1 levels. Therefore, Sp1 phosphorylation is regulated in a growth/cell cycle-dependent manner which correlates temporally with induction of dihydrofolate reductase transcription. Further studies revealed a kinase activity specifically associated with Sp1 in a growth-regulated manner. This activity is distinct from purified kinases previously shown to phosphorylate Sp1 in vitro and phosphorylates Sp1 between amino acids 612 and 678 in its C terminus, a region also phosphorylated in mid-G1 in vivo. Therefore, this study indicates that phosphorylation of the C terminus of Sp1 may play a role in the cell cycle regulation of its transcriptional activity. Sp1 sites can mediate growth/cell cycle induction of dihydrofolate reductase in late G1 (Jensen, D. E., Black, A. R. Swick, A. G., and Azizkhan, J. C. (1997) J. Cell. Biochem. 67, 24–31). To investigate mechanisms underlying this induction, effects of serum stimulation on regulation of Sp1 were examined. In Balb/c 3T3 cells, serum stimulation did not affect Sp1 synthesis or the relative binding of Sp1 family members to DNA; however, it did result in a rapid, ∼2-fold increase in Sp1 levels and an ∼3-fold increase in specific Sp1 phosphorylation in mid-G1. In normal human diploid fibroblasts, serum stimulation also increased Sp1 phosphorylation in mid-G1 but did not affect Sp1 levels. Therefore, Sp1 phosphorylation is regulated in a growth/cell cycle-dependent manner which correlates temporally with induction of dihydrofolate reductase transcription. Further studies revealed a kinase activity specifically associated with Sp1 in a growth-regulated manner. This activity is distinct from purified kinases previously shown to phosphorylate Sp1 in vitro and phosphorylates Sp1 between amino acids 612 and 678 in its C terminus, a region also phosphorylated in mid-G1 in vivo. Therefore, this study indicates that phosphorylation of the C terminus of Sp1 may play a role in the cell cycle regulation of its transcriptional activity. Expression of a large number of genes associated with DNA synthesis, such as dihydrofolate reductase (DHFR), 1The abbreviations used are: DHFR, dihydrofolate reductase; PKA, protein kinase A; NHDF, normal human diploid fibroblasts; PAGE, polyacrylamide gel electrophoresis; GST, glutathioneS-transferase. 1The abbreviations used are: DHFR, dihydrofolate reductase; PKA, protein kinase A; NHDF, normal human diploid fibroblasts; PAGE, polyacrylamide gel electrophoresis; GST, glutathioneS-transferase. is tightly regulated with cell growth and the cell cycle. Many of these genes have promoters which lack a TATAA element but contain binding sites for the transcription factors Sp1 and E2F (1Azizkhan J.C. Jensen D.E. Pierce A.J. Wade M. Crit. Rev. Eukaryotic Gene Exp. 1993; 3: 229-254PubMed Google Scholar). Although the role of E2F sites in growth/cell cycle regulation of transcription and the regulation of E2F by retinoblastoma protein (pRB) and related pocket proteins have been extensively characterized (see Refs. 2Black A.R. Azizkhan J.C. Pezcoller Found. J. 1996; 3: 4-16Google 1996; Google J. J. Cell. Google for a role for Sp1 sites in growth/cell cycle regulation of transcription is to Refs. Google and D.E. A.R. Azizkhan J.C. J. Cell. Biochem. Google Scholar). have that Sp1 and E2F sites have distinct in the growth/cell cycle regulation of the D.E. A.R. Azizkhan J.C. J. Cell. Biochem. Google Scholar). Although of transcription in and G1 E2F its induction in late by Sp1 role of transcription in growth regulation of transcription is by of Sp1 by Refs. A.J. 1993; Google D.E. Google R. A. J. 1993; Google of Sp1 DNA binding activity in D. J. Google and increased Sp1 associated with J. A. 1996; Google is a transcription that in promoters (see Refs. J.C. Jensen D.E. Pierce A.J. Wade M. Crit. Rev. Eukaryotic Gene Exp. 1993; 3: 229-254PubMed Google A.R. Azizkhan J.C. Pezcoller Found. J. 1996; 3: 4-16Google for Although Sp1 been as a transcriptional which as a for an number of studies that transcription is regulated in to a of in to role in growth/cell cycle regulation of Sp1 sites in induction of transcription in to Azizkhan J.C. A. Google induction of transcription in to Google and growth induction of J. Google of transcription by in Sp1 DNA binding activity. Sp1 is and and of these to in its been in in Sp1 binding and transcriptional J. Google J. 1996; Google C. J. J. Google and in the of Cell. Google and its with factors M. J. J. Cell. Google Scholar). that the regulation of Sp1 sites to with the that Sp1 is a of a the members of the not the as Sp1 and is to the on the is and the as Sp1 but a transcriptional activity. Sp1 to an transcription a and can as a transcriptional or on the and cell A.J. Google J. Google J. Google M. 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Cell. 1996; Google J. J. Cell. 1996; Google J. Google not for regulation of Sp1 is which been shown to play a role in the of Sp1 with factors M. J. J. Cell. Google and in regulation of its Cell. Google Scholar). of a role for Sp1 levels in Balb/c 3T3 in Sp1 synthesis, that its levels may regulated by in with the serum stimulation of the phosphorylation of have an kinase with Sp1 is Although that the kinase activity a Sp1 kinase of the and of the effects of its in Google the of the factors in of its of the activity is that the activity with Sp1 of the is the of the activity is specifically associated with Sp1 of the is by the that this activity to of which been with from Sp1 the kinase activity phosphorylates Sp1 in its a region phosphorylated in late G1 in these studies have an kinase that is to in regulation of its the of the kinase is Sp1 been shown to phosphorylated in vitro by PKA, and protein however, the kinase from these kinases in its to and its to and Although it is that the kinase activity kinase phosphorylates sites on Sp1 in the of its by of and to it of the a of the activity. the of this it that protein kinase to an increase in Sp1 activity phosphorylation of in the terminus of Sp1 C. J. Google Scholar). Although this phosphorylation by it on the of the kinase did not phosphorylate the terminus of Sp1 and to of by these that the kinase is distinct from protein Therefore, the kinase activity a growth-regulated Sp1 with the in it is also that PKA, or protein kinase for the increased phosphorylation of Sp1 in G1 in vivo. of Sp1 by to a in Sp1 DNA binding and on J. Google Biochem. Google Scholar). Therefore, G1 phosphorylation of Sp1 is on and in DNA binding were between and G1 cells, is to for the growth/cell phosphorylation of Although to of Sp1 transcription a number of its role in this is phosphorylates Sp1 in vitro and this phosphorylation to increased Sp1 DNA binding C. J. J. Google Scholar). In of in to Sp1 transcription of the in Sp1 levels or DNA binding activity Google and binding to Sp1 sites the is to a Sp1 M. M. J. Google Scholar). increased DNA binding by and the of in the in Sp1 it from the kinase for the G1 phosphorylation protein kinase DNA for activity and been in to DNA Cell. 1993; Google it is to to the of of kinases kinase in phosphorylation of Sp1 is by its phosphorylation in G1 which lack kinase activity Google Scholar). in with the of Sp1 sites in Sp1 is phosphorylated sites by kinases which to in regulation of its activity in to studies the and the of its phosphorylation of is phosphorylated and as a on to of the phosphorylated and R. Cell. Google serum stimulation did not the of these in Balb/c 3T3 or and A.R. A. Azizkhan J.C. Cell. 1996; Google Scholar). Therefore, the phosphorylation of Sp1 in G1 increased phosphorylation of or a of the Sp1 phosphorylation In with the kinase phosphorylated a region of Sp1 its C terminus in to phosphorylation of the terminus of studies revealed phosphorylation in the amino acids of Sp1 in G1 in vivo. to of proteins in cells, it not to phosphorylation of this is related to the of Sp1 phosphorylation in studies in phosphorylation of the of to phosphorylation of the R. Cell. Google Scholar). Although this may cell with the phosphorylation of the C terminus of Sp1 by a kinase it that the C terminus of Sp1 is phosphorylated in G1 region of Sp1 phosphorylated in vitro in the of the of the This region however, to the kinase in it is not to which of these sites of these studies the region of Sp1 which can phosphorylated by the kinase activity. to the binding of Sp1 to DNA M. Google which may for the that Sp1 phosphorylation in G1 not with in the specific DNA binding activity of of between transcription and increased levels or DNA binding of Sp1 that the Sp1 activity is to in its with to phosphorylation of Sp1 in it is that the C terminus of Sp1 been in its with transcription This region of Sp1 is in with protein A. Google Cell. Google and its with Google and with and A.R. A. Azizkhan J.C. Cell. 1996; Google A. 1993; Google factors which can mediate serum induction and cell cycle regulation of transcription A.R. Azizkhan J.C. Pezcoller Found. J. 1996; 3: 4-16Google Google Scholar). the region of Sp1 that with to the region phosphorylated by the kinase activity. A. R. Black, and J. C. Azizkhan, with or can affect transcription in the of binding to DNA A.R. A. Azizkhan J.C. Cell. 1996; Google A. 1993; Google of these by phosphorylation of Sp1 in mediate in Sp1 transcription. Sp1 also been shown to or with cell cycle proteins such as retinoblastoma protein and R. Cell. Google R. Cell. Google A.J. A. Google Cell. Google Scholar). of this region of Sp1 its with factors and the growth/cell cycle regulation of transcription. Expression of a large number of genes associated with DNA synthesis, such as dihydrofolate reductase (DHFR), 1The abbreviations used are: DHFR, dihydrofolate reductase; PKA, protein kinase A; NHDF, normal human diploid fibroblasts; PAGE, polyacrylamide gel electrophoresis; GST, glutathioneS-transferase. 1The abbreviations used are: DHFR, dihydrofolate reductase; PKA, protein kinase A; NHDF, normal human diploid fibroblasts; PAGE, polyacrylamide gel electrophoresis; GST, glutathioneS-transferase. is tightly regulated with cell growth and the cell cycle. Many of these genes have promoters which lack a TATAA element but contain binding sites for the transcription factors Sp1 and E2F (1Azizkhan J.C. Jensen D.E. Pierce A.J. Wade M. Crit. Rev. Eukaryotic Gene Exp. 1993; 3: 229-254PubMed Google Scholar). Although the role of E2F sites in growth/cell cycle regulation of transcription and the regulation of E2F by retinoblastoma protein (pRB) and related pocket proteins have been extensively characterized (see Refs. 2Black A.R. Azizkhan J.C. Pezcoller Found. J. 1996; 3: 4-16Google 1996; Google J. J. Cell. Google for a role for Sp1 sites in growth/cell cycle regulation of transcription is to Refs. Google and D.E. A.R. Azizkhan J.C. J. Cell. Biochem. Google Scholar). have that Sp1 and E2F sites have distinct in the growth/cell cycle regulation of the D.E. A.R. Azizkhan J.C. J. Cell. Biochem. Google Scholar). Although of transcription in and G1 E2F its induction in late by Sp1 role of transcription in growth regulation of transcription is by of Sp1 by Refs. A.J. 1993; Google D.E. Google R. A. J. 1993; Google of Sp1 DNA binding activity in D. J. Google and increased Sp1 associated with J. A. 1996; Google Scholar). Sp1 is a transcription that in promoters (see Refs. J.C. Jensen D.E. Pierce A.J. Wade M. Crit. Rev. Eukaryotic Gene Exp. 1993; 3: 229-254PubMed Google A.R. Azizkhan J.C. Pezcoller Found. J. 1996; 3: 4-16Google for Although Sp1 been as a transcriptional which as a for an number of studies that transcription is regulated in to a of in to role in growth/cell cycle regulation of Sp1 sites in induction of transcription in to Azizkhan J.C. A. Google induction of transcription in to Google and growth induction of J. Google Scholar). of transcription by in Sp1 DNA binding activity. Sp1 is and and of these to in its been in in Sp1 binding and transcriptional J. Google J. 1996; Google C. J. J. Google and in the of Cell. Google and its with factors M. J. J. Cell. Google Scholar). that the regulation of Sp1 sites to with the that Sp1 is a of a the members of the not the as Sp1 and is to the on the is and the as Sp1 but a transcriptional activity. Sp1 to an transcription a and can as a transcriptional or on the and cell A.J. Google J. Google J. Google M. Google Google Google Scholar). role for in regulation of Sp1 transcription is in its of induction A. J. Google Scholar). To the underlying growth/cell induction of Sp1 characterized in Sp1 serum stimulation of stimulation to an increase in Sp1 levels and with the increased phosphorylation with induction of of the in also that this in phosphorylation is by in the of Sp1 with a Sp1 kinase activity which phosphorylates the C terminus of mechanisms underlying the serum induction of Sp1 have the synthesis, and DNA binding of stimulation of Balb/c 3T3 to an increase in Sp1 levels and Sp1 synthesis its specific DNA binding activity increase in Sp1 phosphorylation that of that it in from an increase in the of phosphorylation of Sp1 This in in Sp1 phosphorylation were with increase in protein levels. of the Sp1 binding were not by serum that the induction of transcription is not to in the relative binding of and factors to the Sp1 Therefore, of the in Sp1 levels and phosphorylation for the in of the of these revealed that induction of Sp1 protein levels serum stimulation of Balb/c 3T3 the increase in phosphorylation is and have that the of serum induction of transcription is in Balb/c 3T3 D.E. A.R. Azizkhan J.C. J. Cell. Biochem. Google with or serum In that the is the J. Cell. 1996; Google that Sp1 is not this that the to Sp1 the (see this and indicates that Sp1 levels the This to a for regulation of activity by promoters Sp1 levels the induction of Sp1 levels by serum to induction of with promoters which regulated by Sp1 phosphorylation and Sp1 levels not induction the study it that serum stimulation of to a induction of Sp1 levels and that this correlates with the increase in transcription of C. C. M. J. Biochem. Google Scholar). between this study and in the cell promoters used studies in used a Sp1 which shown activity in studies Azizkhan J.C. Google Although the of phosphorylation to the induction in not it that transcription may regulated levels on the and cell This is by the that Sp1 sites play a role in growth regulation of the the in 3T3 Google and that Sp1 levels binding activity not serum stimulation of 3T3 or human D.E. Google A.R. A. Azizkhan J.C. Cell. 1996; Google J. J. Cell. 1996; Google J. Google not for regulation of Sp1 is which been shown to play a role in the of Sp1 with factors M. J. J. Cell. Google and in regulation of its Cell. Google Scholar). of a role for Sp1 levels in Balb/c 3T3 in Sp1 synthesis, that its levels may regulated by in with the serum stimulation of the phosphorylation of have an kinase with Sp1 is Although that the kinase activity a Sp1 kinase of the and of the effects of its in Google the of the factors in of its of the activity is that the activity with Sp1 of the is the of the activity is specifically associated with Sp1 of the is by the that this activity to of which been with from Sp1 the kinase activity phosphorylates Sp1 in its a region phosphorylated in late G1 in these studies have an kinase that is to in regulation of its the of the kinase is Sp1 been shown to phosphorylated in vitro by PKA, and protein however, the kinase from these kinases in its to and its to and Although it is that the kinase activity kinase phosphorylates sites on Sp1 in the of its by of and to it of the a of the activity. the of this it that protein kinase to an increase in Sp1 activity phosphorylation of in the terminus of Sp1 C. J. Google Scholar). Although this phosphorylation by it on the of the kinase did not phosphorylate the terminus of Sp1 and to of by these that the kinase is distinct from protein Therefore, the kinase activity a growth-regulated Sp1 with the in it is also that PKA, or protein kinase for the increased phosphorylation of Sp1 in G1 in vivo. of Sp1 by to a in Sp1 DNA binding and on J. Google Biochem. Google Scholar). Therefore, G1 phosphorylation of Sp1 is on and in DNA binding were between and G1 cells, is to for the growth/cell phosphorylation of Although to of Sp1 transcription a number of its role in this is phosphorylates Sp1 in vitro and this phosphorylation to increased Sp1 DNA binding C. J. J. Google Scholar). In of in to Sp1 transcription of the in Sp1 levels or DNA binding activity Google and binding to Sp1 sites the is to a Sp1 M. M. J. Google Scholar). increased DNA binding by and the of in the in Sp1 it from the kinase for the G1 phosphorylation protein kinase DNA for activity and been in to DNA Cell. 1993; Google it is to to the of of kinases kinase in phosphorylation of Sp1 is by its phosphorylation in G1 which lack kinase activity Google Scholar). in with the of Sp1 sites in Sp1 is phosphorylated sites by kinases which to in regulation of its activity in to studies the and the of its phosphorylation of is phosphorylated and as a on to of the phosphorylated and R. Cell. Google serum stimulation did not the of these in Balb/c 3T3 or and A.R. A. Azizkhan J.C. Cell. 1996; Google Scholar). Therefore, the phosphorylation of Sp1 in G1 increased phosphorylation of or a of the Sp1 phosphorylation In with the kinase phosphorylated a region of Sp1 its C terminus in to phosphorylation of the terminus of studies revealed phosphorylation in the amino acids of Sp1 in G1 in vivo. to of proteins in cells, it not to phosphorylation of this is related to the of Sp1 phosphorylation in studies in phosphorylation of the of to phosphorylation of the R. Cell. Google Scholar). Although this may cell with the phosphorylation of the C terminus of Sp1 by a kinase it that the C terminus of Sp1 is phosphorylated in G1 region of Sp1 phosphorylated in vitro in the of the of the This region however, to the kinase in it is not to which of these sites of these studies the region of Sp1 which can phosphorylated by the kinase activity. to the binding of Sp1 to DNA M. Google which may for the that Sp1 phosphorylation in G1 not with in the specific DNA binding activity of of between transcription and increased levels or DNA binding of Sp1 that the Sp1 activity is to in its with to phosphorylation of Sp1 in it is that the C terminus of Sp1 been in its with transcription This region of Sp1 is in with protein A. Google Cell. Google and its with Google and with and A.R. A. Azizkhan J.C. Cell. 1996; Google A. 1993; Google factors which can mediate serum induction and cell cycle regulation of transcription A.R. Azizkhan J.C. Pezcoller Found. J. 1996; 3: 4-16Google Google Scholar). the region of Sp1 that with to the region phosphorylated by the kinase activity. A. R. Black, and J. C. Azizkhan, with or can affect transcription in the of binding to DNA A.R. A. Azizkhan J.C. Cell. 1996; Google A. 1993; Google of these by phosphorylation of Sp1 in mediate in Sp1 transcription. Sp1 also been shown to or with cell cycle proteins such as retinoblastoma protein and R. Cell. Google R. Cell. Google A.J. A. Google Cell. Google Scholar). of this region of Sp1 its with factors and the growth/cell cycle regulation of transcription. To mechanisms underlying the serum induction of Sp1 have the synthesis, and DNA binding of stimulation of Balb/c 3T3 to an increase in Sp1 levels and Sp1 synthesis its specific DNA binding activity increase in Sp1 phosphorylation that of that it in from an increase in the of phosphorylation of Sp1 This in in Sp1 phosphorylation were with increase in protein levels. of the Sp1 binding were not by serum that the induction of transcription is not to in the relative binding of and factors to the Sp1 Therefore, of the in Sp1 levels and phosphorylation for the in transcription. of the of these revealed that induction of Sp1 protein levels serum stimulation of Balb/c 3T3 the increase in phosphorylation is and have that the of serum induction of transcription is in Balb/c 3T3 D.E. A.R. Azizkhan J.C. J. Cell. Biochem. Google with or serum In that the is the J. Cell. 1996; Google that Sp1 is not this that the to Sp1 the (see this and indicates that Sp1 levels the This to a for regulation of activity by promoters Sp1 levels the induction of Sp1 levels by serum to induction of with promoters which regulated by Sp1 phosphorylation and Sp1 levels not induction the study it that serum stimulation of to a induction of Sp1 levels and that this correlates with the increase in transcription of C. C. M. J. Biochem. Google Scholar). between this study and in the cell promoters used studies in used a Sp1 which shown activity in studies Azizkhan J.C. Google Although the of phosphorylation to the induction in not it that transcription may regulated levels on the and cell This is by the that Sp1 sites play a role in growth regulation of the the in 3T3 Google and that Sp1 levels binding activity not serum stimulation of 3T3 or human D.E. Google A.R. A. Azizkhan J.C. Cell. 1996; Google J. J. Cell. 1996; Google J. Google Scholar). Although not for regulation of Sp1 is which been shown to play a role in the of Sp1 with factors M. J. J. Cell. Google and in regulation of its Cell. Google Scholar). of a role for Sp1 levels in Balb/c 3T3 in Sp1 synthesis, that its levels may regulated by in In with the serum stimulation of the phosphorylation of have an kinase with Sp1 is Although that the kinase activity a Sp1 kinase of the and of the effects of its in Google the of the factors in of its of the activity is that the activity with Sp1 of the is the of the activity is specifically associated with Sp1 of the is by the that this activity to of which been with from Sp1 the kinase activity phosphorylates Sp1 in its a region phosphorylated in late G1 in vivo. Although these studies have an kinase that is to in regulation of its the of the kinase is Sp1 been shown to phosphorylated in vitro by PKA, and protein however, the kinase from these kinases in its to and its to and Although it is that the kinase activity kinase phosphorylates sites on Sp1 in the of its by of and to it of the a of the activity. the of this it that protein kinase to an increase in Sp1 activity phosphorylation of in the terminus of Sp1 C. J. Google Scholar). Although this phosphorylation by it on the of the kinase did not phosphorylate the terminus of Sp1 and to of by these that the kinase is distinct from protein Therefore, the kinase activity a growth-regulated Sp1 with the in it is also that PKA, or protein kinase for the increased phosphorylation of Sp1 in G1 in vivo. of Sp1 by to a in Sp1 DNA binding and on J. Google Biochem. Google Scholar). Therefore, G1 phosphorylation of Sp1 is on and in DNA binding were between and G1 cells, is to for the growth/cell phosphorylation of Although to of Sp1 transcription a number of its role in this is phosphorylates Sp1 in vitro and this phosphorylation to increased Sp1 DNA binding C. J. J. Google Scholar). In of in to Sp1 transcription of the in Sp1 levels or DNA binding activity Google and binding to Sp1 sites the is to a Sp1 M. M. J. Google Scholar). increased DNA binding by and the of in the in Sp1 it from the kinase for the G1 phosphorylation protein kinase DNA for activity and been in to DNA Cell. 1993; Google it is to to the of of kinases kinase in phosphorylation of Sp1 is by its phosphorylation in G1 which lack kinase activity Google Scholar). in with the of Sp1 sites in Sp1 is phosphorylated sites by kinases which to in regulation of its activity in to studies the and the of its phosphorylation of Sp1 is phosphorylated and as a on to of the phosphorylated and R. Cell. Google serum stimulation did not the of these in Balb/c 3T3 or and A.R. A. Azizkhan J.C. Cell. 1996; Google Scholar). Therefore, the phosphorylation of Sp1 in G1 increased phosphorylation of or a of the Sp1 phosphorylation In with the kinase phosphorylated a region of Sp1 its C terminus in to phosphorylation of the terminus of studies revealed phosphorylation in the amino acids of Sp1 in G1 in vivo. to of proteins in cells, it not to phosphorylation of this is related to the of Sp1 phosphorylation in studies in phosphorylation of the of to phosphorylation of the R. Cell. Google Scholar). Although this may cell with the phosphorylation of the C terminus of Sp1 by a kinase it that the C terminus of Sp1 is phosphorylated in G1 region of Sp1 phosphorylated in vitro in the of the of the This region however, to the kinase in it is not to which of these sites of these studies the region of Sp1 which can phosphorylated by the kinase activity. to the binding of Sp1 to DNA M. Google which may for the that Sp1 phosphorylation in G1 not with in the specific DNA binding activity of of between transcription and increased levels or DNA binding of Sp1 that the Sp1 activity is to in its with to phosphorylation of Sp1 in it is that the C terminus of Sp1 been in its with transcription This region of Sp1 is in with protein A. Google Cell. Google and its with Google and with and A.R. A. Azizkhan J.C. Cell. 1996; Google A. 1993; Google factors which can mediate serum induction and cell cycle regulation of transcription A.R. Azizkhan J.C. Pezcoller Found. J. 1996; 3: 4-16Google Google Scholar). the region of Sp1 that with to the region phosphorylated by the kinase activity. A. R. Black, and J. C. Azizkhan, with or can affect transcription in the of binding to DNA A.R. A. Azizkhan J.C. Cell. 1996; Google A. 1993; Google of these by phosphorylation of Sp1 in mediate in Sp1 transcription. Sp1 also been shown to or with cell cycle proteins such as retinoblastoma protein and R. Cell. Google R. Cell. Google A.J. A. Google Cell. Google Scholar). of this region of Sp1 its with factors and the growth/cell cycle regulation of transcription. members of the Azizkhan in and D. for to this and for with the