Two Functionally Divergent p53-responsive Elements in the Rat Bradykinin B2 Receptor Promoter
Year: 2003
Type: article
Abstract: Although p53 is known to have dual functions as a transcriptional activator and repressor, there has not been an example where both p53-activating and -repressing elements reside within one target promoter. Previous work from this laboratory defined two different p53 response elements, termed P1 and P2, located at nucleotide positions –70 and –707, respectively, in the rat bradykinin B2 receptor promoter. In this study, through manipulation of the DNA sequence and context, we demonstrate opposing roles for P1 and P2 as transcriptional activator and repressor, respectively. Deletion of P1 abrogates p53-mediated activation. P1 maintains its role as an activator upon relocation to the P2 site and activates transcription from a heterologous promoter construct. Thus, P1 is a bona fide positive p53-response element. In contrast, deletion of P2 enhances P1-induced activation. P2 represses transcription when substituted for P1 or when relocated midway between P1 and P2. P2-mediated repression is sequence-dependent, because it is reversed to activation when P2 is substituted by the P1 or p53 consensus sequences. Moreover, site-directed mutagenesis that converts P2 to a higher affinity p53-binding site results in transcriptional activation rather than repression. Surprisingly, P2 strongly activates a heterologous promoter. Thus, P2-mediated transcriptional repression is both sequence- and context-dependent. Investigations into the mechanisms of P2-mediated repression indicate that it is trichostatin-insensitive and unaffected by CBP or mutation of the minimal repression C-terminal domain of p53. However, gel shift assays suggest that p53 competes with other transcriptional activators for binding to overlapping binding sequences within the P2 element. In conclusion, this study provides a rare example of a transcription factor having two divergent functional effects that are sequence- and context-dependent. The interplay of P1 and P2 may be important in the regulation of bradykinin B2 receptor gene expression in response to inflammatory stress and during development. Although p53 is known to have dual functions as a transcriptional activator and repressor, there has not been an example where both p53-activating and -repressing elements reside within one target promoter. Previous work from this laboratory defined two different p53 response elements, termed P1 and P2, located at nucleotide positions –70 and –707, respectively, in the rat bradykinin B2 receptor promoter. In this study, through manipulation of the DNA sequence and context, we demonstrate opposing roles for P1 and P2 as transcriptional activator and repressor, respectively. Deletion of P1 abrogates p53-mediated activation. P1 maintains its role as an activator upon relocation to the P2 site and activates transcription from a heterologous promoter construct. Thus, P1 is a bona fide positive p53-response element. In contrast, deletion of P2 enhances P1-induced activation. P2 represses transcription when substituted for P1 or when relocated midway between P1 and P2. P2-mediated repression is sequence-dependent, because it is reversed to activation when P2 is substituted by the P1 or p53 consensus sequences. Moreover, site-directed mutagenesis that converts P2 to a higher affinity p53-binding site results in transcriptional activation rather than repression. Surprisingly, P2 strongly activates a heterologous promoter. Thus, P2-mediated transcriptional repression is both sequence- and context-dependent. Investigations into the mechanisms of P2-mediated repression indicate that it is trichostatin-insensitive and unaffected by CBP or mutation of the minimal repression C-terminal domain of p53. However, gel shift assays suggest that p53 competes with other transcriptional activators for binding to overlapping binding sequences within the P2 element. In conclusion, this study provides a rare example of a transcription factor having two divergent functional effects that are sequence- and context-dependent. The interplay of P1 and P2 may be important in the regulation of bradykinin B2 receptor gene expression in response to inflammatory stress and during development. The tumor suppressor protein, p53, is a sequence-specific DNA-binding protein (1Kern S.E. Kinzler K.W. Bruskin A. Jarosz D. Friedman P. Prives C. Vogelstein B. Science. 1991; 252: 1708-1711Crossref PubMed Scopus (941) Google Scholar). Classic p53-target genes are involved in regulation of the cell cycle (e.g. p21Waf-1/Cip-1, proliferating cell nuclear antigen, Reprimo, Gadd45, 14-3-3, p22/PRG1, epidermal growth factor receptor) and programmed cell death or apoptosis (e.g. Bax, Fas, p53AIP1, Pidd, Noxa, Caspase-1, Apaf-1, PUMA, KILLER/DR5) (2el-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. 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The consensus p53-binding motif consists of two half-sites separated by 0–13 nucleotides (18Wang L. Wu Q. Qiu P. Mirza A. McGuirk M. Kirschmeier P. Greene J.R. Wang Y. Pickett C.B. Liu S. J. Biol. Chem. 2001; 276: 43604-43610Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 23el-Deiry W.S. Kern S.E. Pietenpol J.A. Kinzler K.W. Vogelstein B. Nat. Genet. 1992; 1: 45-49Crossref PubMed Scopus (1752) Google Scholar). Each half-site consists of the sequence RRRC(A/T)(T/A)GYYY. p53 binds the response element as a tetramer, each half-site bound to a p53 dimer (24McLure K.G. Lee P.W. EMBO J. 1998; 17: 3342-3350Crossref PubMed Scopus (205) Google Scholar). p53 also represses transcription of a number of genes. The mechanisms of p53-mediated repression are not well understood, because the majority of p53-repressed genes do not contain a consensus response element. Although initial studies suggested that p53 selectively represses studies that p53 is of as well C. J. Biol. 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Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Hoffman W.H. R.M. Levine A.J. Genes Dev. PubMed Scopus Google Scholar). In p53 promoter repression DNA binding to a p53-binding as has been in the and genes Lee K. S.A. B. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, S. H. S. D. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, A.J. Mol. Cell. Biol. 19: PubMed Scopus Google Scholar, W.H. S. Chen J. Murphy M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). in one the p53-mediated repression dependent on of an overlapping transcriptional In p53 activation rather than repression of the promoter A.J. Mol. Cell. Biol. 19: PubMed Scopus Google Scholar). In the p53-mediated repression dependent on binding to a novel p53-binding motif in the two of the p53-binding site are in of the site with a site the of p53 from repression to activation K.W. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). the initial that in the p53-response element functional a novel DNA the p53 transcriptional element identified in the promoter of the growth factor gene M. Wang Y. K. Y. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: PubMed Scopus Google Scholar). sequence where is is is or is or and is or from the consensus p53 sequence and represses p53 in a and identified the the bradykinin B2 receptor as a transcriptional target for p53 Z. H. Dipp S. El-Dahr S.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). is a receptor that is involved in the regulation of and renal functions as well as The rat promoter two functional p53-binding a P1 site located at nucleotide positions and P2, located at to the transcription The P1 and P2 sequences or to the p53 consensus sequence and to p53 with affinity (22Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Invest. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar, Z. H. Dipp S. El-Dahr S.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). promoter function suggested that p53 activates the promoter the P1 site and that P2 P1 function Z. H. Dipp S. El-Dahr S.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). However, the mechanisms of such effects not the sequence and and of the P1 and P2 we in this study p53-mediated promoter activation and repression are by the sequence of the p53-response element its In addition, we have of the mechanisms of P2-mediated repression within the of the promoter. The results indicate that the functions of P1 and P2 elements as activator and repressor, respectively, are dependent on DNA Moreover, the function of P2 as a is dependent on its within its promoter p53-mediated repression of P2 is unaffected by and mutation of the minimal repression C-terminal domain of p53 may of transcriptional and in and at in a with in in at in 1 to with of DNA with or the of to for to the and cell a by as for protein or Z. H. Dipp S. El-Dahr S.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). and its the P2 P2, Z. H. Dipp S. El-Dahr S.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). the two as a of and the site-directed mutagenesis The promoter and mutagenesis are in The by the The by P2 at in the construct. to DNA in and at In utilizing of for or for promoter and sequence of mutagenesis p53 or nuclear as (22Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Invest. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar). with with for as in The for at with nuclear and the binding 1 of in to of the to p53 and p53, of The sequences of the in are as P2, W.S. Kern S.E. Pietenpol J.A. Kinzler K.W. Vogelstein B. Nat. Genet. 1992; 1: 45-49Crossref PubMed Scopus (1752) Google and The a p53 a study, we that the rat promoter has two p53-binding sequences located at nucleotide positions –70 and respectively, to the transcription site Z. H. Dipp S. El-Dahr S.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google assays in that expression of p53 transcription of the Deletion has a positive p53-response element in the DNA from to the P1 site at –70 Z. H. Dipp S. El-Dahr S.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). demonstrate that the P1 site of the we the of p53 on the type to with that of a the P1 site The results that of P1 abrogates p53-mediated activation of P1 p53-mediated activation of the promoter the P2 element have that a DNA-binding p53 transcription Z. H. Dipp S. El-Dahr S.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). on we that p53 activation of the promoter the P1 p53-binding the role of we one of the P1 sequence of the in the in p53 a activation of the heterologous promoter construct. activation is not in with In addition, as P1 is of when substituted for P2, the of activation is higher when P1 is located to the promoter with in results and the that P1 is a bona fide positive p53-response element. The P2 and the role of P2, we of the or and a a with deletion and and with Deletion of the P2 site activation and Although the is to p53, the is that P2 strongly represses activation. However, because is to p53 than we that the of the two elements is an important of P1 and P2 of P2 from its at to not p53-mediated and that P2-mediated repression is of the between the P1 and P2 the in P1 substituted by P2 and are by p53 as with and and on we that the of P2 transcriptional repression in response to p53 in the promoter. the deletion is to p53-mediated activation of of from to p53-mediated activation we that an positive p53-responsive element in the between and The function of this element in the of P2 p53-mediated repression P2 is an of the P2 DNA we the P2 sequence in the and with a consensus p53 sequence to the and that of P2 with converts repression to activation. The transcriptional activation by and P1 to be because deletion of P1 the of p53-mediated activation In to P2 deletion or we the effects of P2 mutagenesis or on p53-mediated repression. a P2 a higher binding to p53 than the P2 P2 with p53 be in a we and P2 with nuclear from rat and Z. H. Dipp S. El-Dahr S.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Z. J. H. El-Dahr S.S. J. 2002; PubMed Scopus Google the rat higher of p53 than the to the results p53, the binding of the P2 to nuclear higher than that of the The of p53 in the nuclear is by the by the p53 assays that the and P2 are to p53 than the P2 and mutagenesis that P2-mediated repression is P2 function as a be the of the we P2 of the p53-binding in the construct. in that the a higher than and p53 both well not Moreover, of a P2 site of a minimal promoter in a p53-mediated activation rather than repression the role of P2 as a is of the results of P2 and P1 mutagenesis is in of p53-mediated transcriptional of to both P2 and of p53-mediated transcriptional of to both P2 and of the of p53 P2-mediated C-terminal of p53 an termed Deletion of the or mutagenesis of and p53-mediated repression of the promoter Chen K. Yang Wu J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). to the in P2-mediated repression. this we the effects of or on the transcriptional of and p53 is known to C.V. Brown D.R. Deb S. Deb S.P. Mol. Cell. Biol. 1995; 15: 6785-6793Crossref PubMed Scopus (122) Google we the of mutagenesis on promoter p53 the expression of in a in contrast, p53 In addition, of the p53 not p53-mediated repression of the or the its to transcription at a than the p53 of and of to the promoter by p53 has been to p53 repression of and for P2-mediated repression M. J. Hoffman W.H. R.M. Levine A.J. Genes Dev. PubMed Scopus Google Scholar). may p53. we with a at to p53-mediated transcriptional repression. assays with the p53 and the in with has on P2-mediated repression of the and that p53-mediated repression is by a that is of In the of p53, the of the that p53-mediated activation of the is in the of Z. H. Dipp S. El-Dahr S.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). that P2 with P1 function by for the of P2 having P1 to than with an P2 CBP p53-mediated activation by that of p53 However, the of activation of and not different of p53 to P1 and in the binding affinity of the P1 and P2 elements to p53 at for roles as activator and repressor, respectively. the binding of p53 to P1 and P2 The is by P1 or P2 in a from the of to p53 the affinity of p53 for P1 is higher than P2 the binding of P1 and P2 to rat nuclear The P1 and than of P2. and into other nuclear DNA-binding with p53 the to to P2. transcription factor that the P2 sequence has overlapping binding for and known as utilizing the P2 and and element The P2 is by p53 P1 also competes well P2 for binding. is well by and to a by and not by is by p53 and other is by and by and indicate that P2 is a binding site for transcription p53, and and and suggest that p53 competes with and for binding to the P2 of nuclear protein binding to P2 with P2 with nuclear to the p53 consensus sequence the gene and to the to and indicate the for the sequences of the The study that the transcription factor p53 and a target gene sequence-specific binding to two different In the of the rat the is transcriptional activation as the P1 element the P2 element. of suggest that P1 is a bona fide positive p53-response the minimal promoter to in contrast, a promoter the P1 p53-binding site to is p53-responsive (22Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Invest. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar, Z. H. Dipp S. El-Dahr S.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google deletion of P1 abrogates p53-mediated relocation of P1 (e.g. maintains p53-mediated and P1 activation of a heterologous minimal construct. the that P2 is a sequence-specific with P2 function by or mutagenesis p53-mediated activation P2 represses transcription when substituted for of P2 by a consensus p53-binding sequence converts the repression to and P2 maintains its within the of the promoter of However, of its and in of a P2 as an Thus, the role of P2 is by both its sequence and the of the DNA The mechanisms of p53-mediated transcriptional repression are and not sequence and sequence-specific mechanisms Y. L. C.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, D. Wang Q. A. M. Chen Z. A. G. C. K.G. P. Oncogene. 2000; 19: PubMed Scopus Google Scholar, D.B. B. M. Res. 1996; Google Scholar, N.A. Liu L. N.H. K. K.G. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, Lee K. S.A. B. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, J.M. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Hoffman W.H. R.M. Levine A.J. Genes Dev. PubMed Scopus Google Scholar, S. H. S. D. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, A.J. Mol. Cell. Biol. 19: PubMed Scopus Google Scholar, W.H. S. Chen J. Murphy M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, K.W. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Wang Y. K. Y. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: PubMed Scopus Google Scholar). repression binding to and with transcription binding to an activator (e.g. or or for a repression DNA binding to a p53 response of a (e.g. and for binding with other transcription with overlapping binding results indicate that a on P2-mediated repression. Thus, a role for in or p53 not to be a is not because not p53-repressed genes are also the that P1 and P2 for a such as However, CBP expression in the of P2 on p53-mediated activation. that for CBP is not a p53-mediated repression P2 is by elements in the p53 protein Chen K. Yang Wu J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google have identified a minimal repression domain that p53-mediated transcriptional activation. The to an of the C-terminal of p53. The function of this domain is for p53, because it not activation. of two and to p53-mediated repression of the promoter. into and its effects on transcription from the and its the to P2-mediated the p53 not have such an The results that P2-mediated repression is in the of the p53 a transcriptional than p53, results suggest that p53-mediated repression P2 is not dependent on the Although the is the site of binding by the protein and the protein, the of repression by repression may be to repression with of p53 than to sequence-specific repression. p53-mediated repression of the gene is not by mutation or deletion within the C-terminal the W.H. S. Chen J. Murphy M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). In the of the P2 our results that p53 in a sequence-specific and function is with the important of this study is that P2 repression of promoter of or not P1 is and of the between P1 and P2. because of P2 with P1 or the p53 consensus sequence strongly activates transcription and mutagenesis of P2 its p53-binding and enhances we suggest that P2-mediated repression of the promoter is because P2 represses P2-mediated repression be to with P1 However, because P2 rather than a minimal we that P2-mediated repression is and suggest that sequences within and the P2 site in the promoter a role in the of P2 function as a The studies have also to a p53-response element in the promoter. is because the promoter both the P2 and P1 is by p53 of the is not by p53, we that one or p53-responsive elements reside of nucleotide of the promoter. deletion of the from to in the p53-mediated activation. studies to be to this new p53-responsive element. is important to and in the functional of P1 and P2. in gel shift P1 and P2 p53 with different when nuclear are the and of are different from of the P1 higher affinity and than P2 the of the P1 and P2 are In this it is to that binding of p53 to P1 DNA of the or that P1 p53 with a P2 that is suggested by the results is that p53 competes with other transcription (e.g. and for binding to the P2 may to P2-mediated repression. The of p53-mediated regulation of the gene is to be during p53 with in renal and nuclear p53 are higher in than as are (22Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Invest. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar, Z. J. H. El-Dahr S.S. J. 2002; PubMed Scopus Google Scholar). on expression in the (22Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Invest. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar). Thus, p53 may the expression of the is not the interplay between P1 and P2 P1 is between and P2 is the that the gene has to p53 during P2 to activation of the gene during In the rat gene a rare example of a gene that is by a transcription factor sequence-specific DNA binding. Although with than one functional p53-binding site have been (e.g. and A. A. M. Oncogene. 1995; Google the of two divergent p53-binding elements within the promoter is a novel a to p53 activates or represses gene transcription in the of the promoter. this may to the divergent p53-mediated transcriptional are (e.g. DNA R. G. and B. Vogelstein for of and for of the
Source: Journal of Biological Chemistry
Institution: Tulane University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
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