Key points are not available for this paper at this time.
Nuclear respiratory factor 1 (NRF-1) is a transcriptional activator that acts on a diverse set of nuclear genes required for mitochondrial respiratory function in mammalian cells. These genes encode respiratory proteins as well as components of the mitochondrial transcription, replication, and heme biosynthetic machinery. Here, we establish that NRF-1 is a phosphoprotein in vivo. Phosphorylation occurs on serine residues within a concise NH2-terminal domain with the major sites of phosphate incorporation at serines 39, 44, 46, 47, and 52. The in vivo phosphorylation pattern can be approximated in vitro by phosphorylating recombinant NRF-1 with purified casein kinase II. Phosphate incorporation at the sites utilized in vivo results in a marked stimulation of DNA binding activity which is not observed in mutated proteins lacking these sites. Pairwise expression of the wild-type protein with each of a series of truncated derivatives in transfected cells results in the formation of a dimer between wild-type and mutant forms demonstrating that a homodimer is the active binding species. Although NRF-1 can dimerize in the absence of DNA, phosphorylation does not enhance the formation of these dimers. These findings suggest that phosphorylation results in an intrinsic change in the NRF-1 dimer enhancing its ability to bind DNA. Nuclear respiratory factor 1 (NRF-1) is a transcriptional activator that acts on a diverse set of nuclear genes required for mitochondrial respiratory function in mammalian cells. These genes encode respiratory proteins as well as components of the mitochondrial transcription, replication, and heme biosynthetic machinery. Here, we establish that NRF-1 is a phosphoprotein in vivo. Phosphorylation occurs on serine residues within a concise NH2-terminal domain with the major sites of phosphate incorporation at serines 39, 44, 46, 47, and 52. The in vivo phosphorylation pattern can be approximated in vitro by phosphorylating recombinant NRF-1 with purified casein kinase II. Phosphate incorporation at the sites utilized in vivo results in a marked stimulation of DNA binding activity which is not observed in mutated proteins lacking these sites. Pairwise expression of the wild-type protein with each of a series of truncated derivatives in transfected cells results in the formation of a dimer between wild-type and mutant forms demonstrating that a homodimer is the active binding species. Although NRF-1 can dimerize in the absence of DNA, phosphorylation does not enhance the formation of these dimers. These findings suggest that phosphorylation results in an intrinsic change in the NRF-1 dimer enhancing its ability to bind DNA. Mitochondrial respiratory function requires the expression of essential gene products from both nuclear and mitochondrial genetic systems. Because of its compact structure and limited coding capacity, the mitochondrial genome encodes only 13 proteins along with the tRNAs and rRNAs required for their translation (for review, see Ref. 2Attardi G. Schatz G. Annu. Rev. Cell Biol. 1988; 4: 289-333Crossref PubMed Scopus (1111) Google Scholar). All of these proteins are subunits of the inner membrane respiratory complexes. Thus, nuclear genes must specify the majority of respiratory subunits and all of the proteins required for the expression, maintenance, and replication of mitochondrial DNA (for review, see Ref.8Clayton D.A. Annu. Rev. Cell Biol. 1991; 7: 453-478Crossref PubMed Scopus (540) Google Scholar). One approach to understanding nucleo-mitochondrial interactions in mammalian cells is to identify the nuclear transcription factors that govern the expression of these genes. NRF-1 1The abbreviations used are: NRF-1, nuclear respiratory factor 1; HA, hemagglutinin; CKII, casein kinase II; SRF, serum response factor; MEF2C, myocyte enhancer factor 2C; PAGE, polyacrylamide gel electrophoresis. was originally identified as a nuclear transcription factor that acts on mammalian genes encoding cytochromec and a number of other respiratory proteins (4Evans M.J. Scarpulla R.C. J. Biol. Chem. 1989; 264: 14361-14368Abstract Full Text PDF PubMed Google Scholar, 6Evans M.J. Scarpulla R.C. Genes Dev. 1990; 4: 1023-1034Crossref PubMed Scopus (347) Google Scholar, 10Chau C.A. Evans M.J. Scarpulla R.C. J. Biol. Chem. 1992; 267: 6999-7006Abstract Full Text PDF PubMed Google Scholar). A possible role for the factor in intergenomic communication is supported by the discovery of functional NRF-1 recognition sites in nuclear genes specifying the rate-limiting heme biosynthetic enzyme, 5-aminolevulinate synthase (14Braidotti G. Borthwick I.A. May B.K. J. Biol. Chem. 1993; 268: 1109-1117Abstract Full Text PDF PubMed Google Scholar), and components of the mitochondrial transcription and replication machinery (6Evans M.J. Scarpulla R.C. Genes Dev. 1990; 4: 1023-1034Crossref PubMed Scopus (347) Google Scholar, 18Virbasius J.V. Scarpulla R.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1309-1313Crossref PubMed Scopus (642) Google Scholar, 22Scarpulla R.C. Trends Cardiovasc. Med. 1996; 6: 39-45Crossref PubMed Scopus (62) Google Scholar). The latter include the RNA subunit of mitochondrial RNA processing endonuclease, an enzyme implicated in the formation of mtDNA replication primers and mtTFA, an activator of mitochondrial transcription (for review, see Refs. 8Clayton D.A. Annu. Rev. Cell Biol. 1991; 7: 453-478Crossref PubMed Scopus (540) Google Scholar and16Shadel G.S. Clayton D.A. J. Biol. Chem. 1993; 268: 16083-16086Abstract Full Text PDF PubMed Google Scholar). These findings led to a model whereby NRF-1, along with other transcription factors, helps coordinate the synthesis and function of respiratory proteins from both genomes (6Evans M.J. Scarpulla R.C. Genes Dev. 1990; 4: 1023-1034Crossref PubMed Scopus (347) Google Scholar, 18Virbasius J.V. Scarpulla R.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1309-1313Crossref PubMed Scopus (642) Google Scholar, 22Scarpulla R.C. Trends Cardiovasc. Med. 1996; 6: 39-45Crossref PubMed Scopus (62) Google Scholar). In addition, it has been postulated that NRF-1 may play a role in other developmental and growth regulatory processes (10Chau C.A. Evans M.J. Scarpulla R.C. J. Biol. Chem. 1992; 267: 6999-7006Abstract Full Text PDF PubMed Google Scholar, 17Virbasius C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar). Most notably, the chicken homolog of NRF-1 has recently been associated with the expression of the histone H5 gene during erythrocyte development (21Gomez-Cuadrado A. Martin M. Noel M. Ruiz-Carrillo A. Mol. Cell. Biol. 1995; 15: 6670-6685Crossref PubMed Google Scholar). NRF-1 has been purified and a cDNA clone isolated and characterized (10Chau C.A. Evans M.J. Scarpulla R.C. J. Biol. Chem. 1992; 267: 6999-7006Abstract Full Text PDF PubMed Google Scholar, 17Virbasius C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar). The protein is related through a novel DNA binding domain to developmental regulatory proteins from sea urchins (12Calzone F.J. Hoog C. Teplow D.B. Cutting A.E. Zeller R.W. Britten R.J. Davidson E.H. Development. 1991; 112: 335-350Crossref PubMed Google Scholar) andDrosophila (13Desimone S.M. White K. Mol. Cell. Biol. 1993; 13: 3641-3949Crossref PubMed Scopus (84) Google Scholar). This highly DNA binding domain is in the NH2-terminal of the and the its NH2-terminal through a a nuclear C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google S. Virbasius C.A. Scarpulla R.C. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar). A domain in NRF-1 is required for transcriptional and is not in the proteins S. Virbasius C.A. Scarpulla R.C. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar). Here, we establish that a concise NH2-terminal domain in NRF-1 as a for phosphorylation in vivo and in The phosphorylation occurs on serine residues and DNA binding Although the a required for NRF-1 phosphorylation does not the in the absence of DNA. phosphorylation to an intrinsic change in the NRF-1 dimer enhancing its DNA The used for in of expression been C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar, S. Virbasius C.A. Scarpulla R.C. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar). was used to This encodes residues and a between for which used to clone it to from C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar) and from S. Virbasius C.A. Scarpulla R.C. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar), from which the NRF-1 been the sites of This in which the coding of NRF-1 was with residues by the This along with from which the NRF-1 NH2-terminal was and sites of 1990; PubMed Scopus Google Scholar) to the expression NRF-1 with the was in a encodes the and a between and which used to clone it to from encoding the of NRF-1 was with the in from was to a and a both from This led to the of the coding of NRF-1 in with the the to the expression the the was This has an the coding for the and an the the recognition for that This was the and sites of the in This a a with the and a at the of the was with as with and of within sites to This the and a at the of the The was from by and used to the within the sites in to The NH2-terminal 1 and by The was used along with the are to the of the NRF-1 cDNA C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar). and a translation within was with with as the The products and in the NRF-1 coding and these the sites in the These encode the NH2-terminal of 1 and These to the from the NRF-1 coding as well as the and the and sites of that in residues are and is by In residues are for 1 and in in A was at of the in the of the This that the NH2-terminal of 1 and These to a from the NRF-1 coding as well as the and the sites of a by the of an within its The mutant expression from C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar, S. Virbasius C.A. Scarpulla R.C. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar). a expression the the the of in was by the from the expression the encoding the NH2-terminal of NRF-1 in was by the from by an from encoding the of This was by the of Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The mutated was used to the in to expression with the expression as 1990; PubMed Scopus Google Scholar). and recombinant protein was purified by as M. 1991; PubMed Scopus Google Scholar). This purified was purified by as by the proteins from the by and at for of and cells been Scarpulla R.C. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). cells transfected by phosphate as PubMed Scopus Google Scholar, J.V. Scarpulla R.C. Mol. Cell. Biol. 1991; PubMed Scopus Google Scarpulla R.C. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). cells transfected in as by the vivo transfected cells and with of of was and cells for for of NRF-1, cells to in a and with of was and cells for for All at cells on with and for with 1 as and 1 1 as The was at for to The was for 1 with of with and serum protein was and the with for 1 The by at for 1 and with The in to for and to as to a as by the at in of NRF-1 and in with at in for 1 at in with at in for 1 at with the in and proteins with an as by the with NRF-1 and in and in the in was to These proteins with the at by at NRF-1 and derivatives with recombinant at in and 1 of for the of phosphate NRF-1 a of was A of the proteins was with The on membrane and with The in and incorporation by The for incorporation by the recombinant in of the NRF-1 dimer 1 of recombinant protein was on a polyacrylamide gel and with recombinant proteins in serum and at in vitro from cells on and to (for (for as proteins by from in 1989; PubMed Scopus Google Scholar). by at and on PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) the as by the from in at with of as J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). from with an of and a The gel was and by used for in been and NRF-1 binding sites from the subunit and mitochondrial transcription factor A genes M.J. Scarpulla R.C. Mol. Cell. Biol. 1988; PubMed Scopus Google Scholar, M.J. Scarpulla R.C. J. Biol. Chem. 1989; 264: 14361-14368Abstract Full Text PDF PubMed Google Scholar, 6Evans M.J. Scarpulla R.C. Genes Dev. 1990; 4: 1023-1034Crossref PubMed Scopus (347) Google Scholar, 10Chau C.A. Evans M.J. Scarpulla R.C. J. Biol. Chem. 1992; 267: 6999-7006Abstract Full Text PDF PubMed Google Scholar, 18Virbasius J.V. Scarpulla R.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1309-1313Crossref PubMed Scopus (642) Google Scholar). Nuclear from transfected cells as 1991; PubMed Scopus Google Scholar). with these as J.V. Scarpulla R.C. Mol. Cell. Biol. 1991; PubMed Scopus Google C.A. Evans M.J. Scarpulla R.C. J. Biol. Chem. 1992; 267: 6999-7006Abstract Full Text PDF PubMed Google Scholar). with recombinant NRF-1 and in of of of DNA, of recombinant and of that was the of DNA at for on polyacrylamide in and by of the in binding activity of and forms of NRF-1, of recombinant protein was used with DNA and of The from and was a of the of NRF-1 a number of phosphorylation sites. NRF-1 is a phosphoprotein in the protein was from in vivo A at the was gel of was with serum that the protein is NRF-1, the was cells transfected with a NRF-1 expression the lacking the NRF-1 coding as a A was in from cells transfected with the NRF-1 expression 1 to transfected with the for from the Thus, the NRF-1 protein from both and transfected genes is in vivo phosphorylation of NRF-1 from and transfected genes. cells 1 and cells transfected with an expression with a NRF-1 expression with cells and was with serum serum and by to NRF-1 in cells and NRF-1 in transfected cells. to are at the 1 and NRF-1 and from A was with 1 and and and by NRF-1 from A was with and for as in was at and in at with the at the of and was of to the protein from the is on the sites as the the NRF-1 proteins that been to gel to a major for both and transfected proteins 1 and a pattern of which was between protein and was on and transfected proteins to the residues In both was the along with of 1 Thus, phosphorylation of the protein from the is from that of the NRF-1 protein in vivo. A phosphorylation sites for within the NH2-terminal of identify phosphorylation NH2-terminal from and their ability to as for phosphorylation was by of The that of the is at the of the This the protein to be with a the A in phosphorylation was of serine and residues to and serine of serines and by to in a protein that is only in vivo of the serine and residues in the NH2-terminal domain by to in a in of the the that the wild-type and mutated proteins are in Thus, the observed not from in the expression the results expression of the series in cells with the that a phosphorylation in in cells These along with the of as the that major in vivo phosphorylation sites are to serines The of the residues was by all serine and phosphorylation sites within the NH2-terminal domain to by These include all serines between residues 1 and and the and which phosphorylation sites. was to wild-type in expression and the ability of each to be was by and The for these proteins that of the are at the of the This the protein to be from the protein and with a the of all residues in the phosphorylation of NRF-1 from the This the results with NH2-terminal and that the major phosphorylation sites within a concise NH2-terminal domain residues of each of the sites that serines 39, 44, and are the major phosphorylation sites and serines and and may be sites. the that is for transfected proteins that in expression, by are to for the in phosphorylation These results are with the with the NH2-terminal The with the results is that serine is at of in cells a which results from phosphorylation of In addition, serine to be well in cells. This may from of expression of the from a The of NRF-1 phosphorylation does not with required for DNA nuclear transcriptional C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar, S. Virbasius C.A. Scarpulla R.C. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar). the functional of phosphorylation it is to the in pattern in an in vitro Because of the sites the for phosphorylation by C. D.A. C. J. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar), enzyme was purified recombinant NRF-1 proteins from the wild-type and mutated derivatives of NRF-1 as The results with the proteins in transfected cells. was that can of of wild-type NRF-1 This was to in in and in that the enzyme acts on the NH2-terminal domain in vivo. The major between the in vivo and in vitro results is that is to a in vitro not in vivo. that is NH2-terminal in of and in along with the of phosphorylation in of phosphate of that the phosphorylation observed vitro results from the phosphorylation of a serine and a between and This is by the that of all serine residues in the NH2-terminal domain the incorporation of phosphate to of which was to in These are with the that the serines that are in vivo. the enzyme is to at 1 serine and 1 between and This is with the phosphorylation of serine as well as the phosphorylation of in cells One is that phosphorylation may NRF-1 function by its ability to bind DNA. the DNA binding of the and forms of the wild-type and mutant proteins The results a marked stimulation of the NRF-1 DNA binding activity by phosphorylation 1 of forms of NRF-1 with of The results that at protein is This stimulation is in 1 and and is in and which the major serine phosphorylation sites utilized in vivo and in and which is not The of serine phosphorylation is by the absence of a on DNA binding in which the phosphorylation with which is not is not in The of NRF-1 DNA binding was observed recognition sites from genes 1 and subunit 1 and and and mitochondrial transcription factor A The results are with the that serine residues 39, 44, 46, 47, and as for that can NRF-1 DNA binding The NRF-1 binding is a of (6Evans M.J. Scarpulla R.C. Genes Dev. 1990; 4: 1023-1034Crossref PubMed Scopus (347) Google Scholar, 17Virbasius C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar) that the protein DNA as a is the phosphorylation may DNA binding by subunit a dimer is the a series of truncated derivatives of NRF-1 was and NH2-terminal in transfected and nuclear for DNA binding to the NRF-1 to residues and and NH2-terminal to residues and all DNA binding activity to that of the wild-type protein and The at to wild-type as by with serum The was a to which was was to bind DNA This is with results which the of the DNA binding domain between residues and C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar). NRF-1 DNA as a of the wild-type protein with each of the truncated derivatives to mutant and the other NRF-1 its recognition as a be the wild-type the mutant and a between mutant and in of the wild-type with each of the mutated proteins that are of binding DNA complexes. The in each to that the wild-type protein The to that each In each the between the is with the formation of a that these from expression of of each mutant and wild-type in the nuclear from transfected cells These results establish that NRF-1 its DNA recognition as a phosphorylation DNA binding by enhancing the of the the of phosphorylation on the subunit of wild-type and mutated proteins was by gel electrophoresis. of the NRF-1 dimer was NH2-terminal to with in the absence of the wild-type protein was was The 1 and as of and dimer The results in the of the absence of the enzyme Thus, an NH2-terminal domain between residues 1 and is required for NRF-1 to its structure in the absence of DNA. This domain with all of the major sites of serine of phosphorylation on dimer the wild-type and mutated proteins with in the of these phosphorylation on the of and dimer on of the DNA binding of the major serine phosphorylation sites and in which all of the serine and phosphorylation sites are to is in its from wild-type in the absence of that phosphorylation of these residues is not essential for dimer phosphorylation DNA binding dimer formation in the absence of DNA. The of to a role for NRF-1 in nucleo-mitochondrial interactions in mammalian cells (6Evans M.J. Scarpulla R.C. Genes Dev. 1990; 4: 1023-1034Crossref PubMed Scopus (347) Google Scholar, 17Virbasius C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar, 18Virbasius J.V. Scarpulla R.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1309-1313Crossref PubMed Scopus (642) Google Scholar). NRF-1 sites are in the majority of nuclear genes encoding respiratory subunits and in genes required for mitochondrial transcription, replication, and heme R.C. Trends Cardiovasc. Med. 1996; 6: 39-45Crossref PubMed Scopus (62) Google Scholar). In addition, NRF-1 may a role in coordinate gene expression by on genes encoding components in the of and (10Chau C.A. Evans M.J. Scarpulla R.C. J. Biol. Chem. 1992; 267: 6999-7006Abstract Full Text PDF PubMed Google Scholar, 17Virbasius C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar). in NRF-1 which are required for its function been A DNA binding domain within the NH2-terminal of the is highly in a of regulatory proteins which the sea factor and the gene C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar). These proteins are required for development in their The domain is not In NRF-1, domain of residues that are required for transcriptional S. Virbasius C.A. Scarpulla R.C. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar). In to the DNA binding with is between residues and of the in has been to a nuclear from the DNA binding domain (21Gomez-Cuadrado A. Martin M. Noel M. Ruiz-Carrillo A. Mol. Cell. Biol. 1995; 15: 6670-6685Crossref PubMed Google Scholar, S. Virbasius C.A. Scarpulla R.C. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar). other been to the of Here, we establish that NRF-1 is a phosphoprotein and that in vivo phosphorylation occurs within a concise NH2-terminal domain on serine residues 39, 44, 46, 47, and 52. of the serines 44, 46, and are in it is are in sea All serines to the for phosphorylation by C. D.A. C. J. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar) the can be and the purified enzyme these sites in All are by that are in and all serine the at the In the serine it is that the at is by Although is the for the in the in vivo and in are not The major is that the between residues and is in vitro it is in vivo. The of phosphorylation that on a In to serine which is in and to the These residues can for the in phosphorylation in wild-type and mutated Thus, it is that these residues are to phosphorylation in the in vitro is to that phosphorylation by does not to DNA that majority of sites which are both in vivo and in vitro can for the of phosphorylation on NRF-1 DNA binding The formation of NRF-1 in transfected cells both wild-type and proteins that the protein DNA as a This is with the in the NRF-1 recognition (6Evans M.J. Scarpulla R.C. Genes Dev. 1990; 4: 1023-1034Crossref PubMed Scopus (347) Google Scholar, 17Virbasius C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (287) Google Scholar). Although results in as and dimer on to in vitro by proteins This has been observed with the chicken homolog of NRF-1 and has been to a for the homodimer (21Gomez-Cuadrado A. Martin M. Noel M. Ruiz-Carrillo A. Mol. Cell. Biol. 1995; 15: 6670-6685Crossref PubMed Google Scholar). of wild-type and proteins in the in transfected cells subunits and results in the of Here, we that the of the NRF-1 dimer in the absence of DNA is NH2-terminal to to the on is This that a of is in the NH2-terminal of the protein from the DNA binding a protein with the DNA as a can with wild-type on DNA and can be to a dimer with that the protein does to bind DNA the which is with of a This is in with the results with chicken NRF-1 which suggest an between DNA binding and between residues and (21Gomez-Cuadrado A. Martin M. Noel M. Ruiz-Carrillo A. Mol. Cell. Biol. 1995; 15: 6670-6685Crossref PubMed Google Scholar). that the NH2-terminal domain identified is essential for subunit interactions in the absence of DNA. In addition, within the DNA binding domain a of for DNA binding and for with we that phosphorylation DNA binding by dimer of all NH2-terminal phosphorylation sites by does not in to on This that phosphorylation DNA binding at the of One that the of DNA binding in an ability of wild-type NRF-1 to transcription with wild-type NRF-1 and for their ability a expression was by of the NRF-1 binding from the cytochromec gene of a in in cells S. Virbasius C.A. Scarpulla R.C. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar). In both proteins transcription by that of an The absence of a between these of results from the that the NRF-1 at can bind DNA and has an may for its DNA binding activity to that of the wild-type transcription factors are to be at sites both in vivo and in In NRF-1 a number of with factors, and 1993; Google Scholar, A. J. 1992; PubMed Scopus Google Scholar, C. J. J. 1992; PubMed Scopus Google Scholar, Genes Dev. 1990; 4: PubMed Scopus Google Scholar) and J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) NRF-1 in that phosphorylation of a number of serine residues to the of the which DNA for factor binding to their recognition sites. In SRF, of serine residues in in both its and to the that phosphorylation does not the binding for DNA A. J. 1992; PubMed Scopus Google Scholar, C. J. J. 1992; PubMed Scopus Google Scholar). that phosphorylation results in a marked in the of of NRF-1 from DNA, and C. that its on DNA may be of the essential serines to in both and the on DNA binding as In addition, phosphorylation does not the ability of to dimerize Mol. Cell. Biol. 1991; PubMed Scopus Google Scholar) of to with other transcription factors J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). In both it has been postulated that of a may a change that the DNA binding domain J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Mol. Cell. Biol. 1991; PubMed Scopus Google Scholar). a is with the that NRF-1 phosphorylation DNA binding the between These suggest that SRF, MEF2C, and NRF-1 may be for the of NRF-1 function by phosphorylation is an the role for the factor in interactions and the of other growth regulatory Although activity is by serum growth factors (for review, see Ref. Mol. Cell. 1993; Scopus Google Scholar) is that stimulation to the of gene expression through the of transcription change in the of the of has been in response to growth factor expression of a mutant that its recognition at on expression 1993; Google Scholar). phosphorylation of the sites in the binding factor the of their RNA genes. In addition, the of binding factor not its of expression, is in to serum and with RNA transcription A. A. J. 1992; PubMed Scopus Google Scholar, J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar). One is that phosphorylation of transcription factors as NRF-1 by related occurs in response to that the respiratory of the to the nuclear transcriptional a may the expression of nuclear genes to the of respiratory The results an essential in understanding the role of phosphorylation in gene
Gugneja et al. (Tue,) studied this question.
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