COMMUNICATION
Differential Regulation of p53-dependent and -independent Proliferating Cell Nuclear Antigen Gene Transcription by 12 S E1A Oncoprotein Requires CBP*

Sankunny M. KaruppayilDagger , Elizabeth Moran§, and Gokul M. DasDagger parallel

From the Dagger  Cancer Therapy and Research Center and  Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, Texas 78229 and the § Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

    ABSTRACT
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Abstract
Introduction
Procedures
Results & Discussion
References

The tumor suppressor protein p53 and the adenoviral 12 S E1A oncoprotein are both known to elicit their biological effects mainly by regulating the transcription of important cellular genes. The human proliferating cell nuclear antigen (PCNA) gene is a transcriptional target of both p53 and E1A. We have analyzed the effects of p53 and 12 S E1A, separately as well as together, on PCNA gene transcription. Our results showed that whereas both p53 and 12 S E1A separately activated PCNA transcription, 12 S E1A repressed p53-mediated transcriptional activation. Thus, 12 S E1A uses a dual strategy of transcriptional activation and repression to take control of the cellular PCNA gene regulation. The cyclic AMP-response element in the PCNA core promoter, besides being crucial for basal transcription, synergizes with p53 to activate transcription. The cyclic AMP response element-binding protein (CREB)-binding protein (CBP) is an essential component of both the transcriptional activation and repression by E1A. Our data demonstrate for the first time that E1A can modulate CBP function to activate PCNA transcription, while at the same time repressing p53-mediated activation by disrupting CBP interaction with p53, thereby uncoupling PCNA transcription from the regulatory effects of p53.

    INTRODUCTION
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Abstract
Introduction
Procedures
Results & Discussion
References

It is becoming increasingly evident that the tumor suppressor protein p53 elicits its biological effects as a cell cycle checkpoint molecule mainly by regulating transcription of important genes (1, 2). Similarly, the adenovirus 12 S E1A oncoprotein is a multifunctional protein whose cellular effects are mediated principally through its ability to modulate the transcriptional activity of various target genes (3). E1A is known to activate certain cellular genes, while repressing others. The human proliferating cell nuclear antigen (PCNA)1 gene is activated by both 13 and 12 S E1A (4, 5) oncoproteins.

PCNA plays an essential cellular role as a component of the DNA replication and repair machinery. From recent studies, it appears that PCNA may function as a communication link between important cellular processes such as DNA replication, DNA repair, and cell cycle control (6). Importantly, p21, another cell cycle regulatory protein, when up-regulated at the transcriptional level by p53 in response to DNA damage, associates with PCNA and inhibits DNA replication while allowing DNA repair to proceed (6, 7). Thus p21 and PCNA are components of the cell cycle checkpoint controlled by p53. 12 S E1A inhibits the activation of p21 by p53, thereby compromising the G1 arrest (8, 9). However, the effect of E1A on the transcriptional activation of PCNA by p53 remains unknown. The studies reported here address how 12 S E1A affects transcriptional activation of PCNA by p53.

The NH2-terminal region of E1A, together with a subdomain of conserved region 1 (CR1), targets the p300/CBP family of cellular proteins, and this interaction is sufficient to promote entry into the S phase of the cell cycle (10). Furthermore, it is well documented that this interaction severely compromises the transcriptional coactivator function of p300/CBP (11-13). E1A proteins have been reported to inhibit transcriptional activation by p53 (9), and E1A elicits this inhibitory effect through its p300/CBP-interacting region (8). Cellular p53 is known to activate PCNA gene transcription (14, 15), whereas high levels of p53 inhibit transcription (14-16), probably by titrating out an important cofactor(s). Recently, using other promoter systems, p300/CBP was shown to interact with p53 and function as an important cofactor in p53-mediated transcriptional activation; 12 S E1A, by virtue of its ability to bind p300/CBP, can disrupt the transcriptional function of p53 (17-20). On the other hand, using GAL4 reporter constructs, it was shown that 12 S E1A, through its interaction with p300, activates transcription by relieving transcriptional repression by YY1 (21). However, it was unclear how 12 S E1A would affect p53-mediated transcriptional regulation of a natural p53 target gene known to be positively regulated by E1A.

To investigate the mechanisms by which E1A interferes with p53-regulated transcription of a cellular gene, we analyzed transcriptional regulation of the human PCNA gene promoter, known to be activated by both E1A and p53. Consistent with earlier results, we found that both 12 S E1A and p53 separately activated PCNA gene transcription in Saos-2 cells. Surprisingly, in the presence of 12 S E1A, p53-mediated transcriptional activation was reduced to the much lower level of activation produced by E1A itself. Furthermore, we show that CBP is involved both in E1A-mediated and p53-mediated transcriptional activation of the PCNA gene. Moreover, CBP is at least one of the factors targeted by E1A in the process of repressing p53-activated PCNA transcription. We have also identified a synergism between CRE, a PCNA core promoter element, and p53 to activate transcription.

    EXPERIMENTAL PROCEDURES
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Abstract
Introduction
Procedures
Results & Discussion
References

Plasmids--  -1265 PCNA luc. was constructed by ligating the -1265/+62 XhoI-HindIII fragment from -1265 PCNA chloramphenicol acetyltransferase (4) to the pGL3-Basic vector (Promega) linearized with XhoI and HindIII. The CRE mutant PCNA promoter was made by the "QuikChange" site-directed mutagenesis method (Stratagene). Complementary oligonucleotides used were 5'-GGACAGCGTGtTGgatcCGCAACGCG-3' and 5'-CGCGTTGCGgatcCAaCACGCTGTCC-3', where the mutant bases are in lowercase. The wild type human p53 expression constructs, pRc/CMV hp53 and the mutant p53 plasmid pRc/CMV hp53-22/23 (22), were obtained from A. J. Levine. The CBP expression plasmid pRc/RSV-CBP (23) was from R. Goodman. pSRalpha -antisense CBP and pSRalpha plasmids (24) were kindly provided by S. Ishii. The E1A expression constructs (12 S wild type, Delta 2-36, and YH47/928) (10), and 12 S E1A.FS (25), were described previously.

Cell Culture-- Saos-2 cells were obtained from American Type Culture Collection (ATCC) and maintained in Dulbecco's modified Eagle's medium (Cellgro/Mediatech) supplemented with 10% fetal bovine serum (Life Technologies, Inc.) at 37 °C under a humidified atmosphere of 5% CO2.

Transcription Assay in Vivo-- For transient expression assays, Saos-2 cells were transfected by the calcium phosphate coprecipitation procedure as described (26). 1.2 × 105 cells on each of the six-well flat bottom culture plates (Falcon) were transfected with -1265 PCNA luc. reporter (1 µg) along with various expression constructs, as noted in the legends for Figs. 1-4, after making up the total DNA concentration to 2.5 µg with pUC119. Cells were washed, and fresh medium was added at 20 h after transfection. Cells were harvested 44 h posttransfection. Luciferase assay was performed according to the protocol of the supplier (Promega). Cells on each well were lysed in 1 ml of lysis buffer, and 10 µl of the lysate was used for assaying the luciferase activity in a TD-20/20 luminometer (Turner Designs). Several independent transfections were performed to ensure reproducibility and, of these, results from three typical transfections are depicted in figures. To confirm that the transcripts were properly initiated, RNA isolated from parallel transfection samples was subjected to RNase protection assay as described previously (26), using riboprobes abutting the transcriptional start site of the PCNA promoter.

Protein Analysis-- 4 × 105 transfected cells were washed with phosphate-buffered saline, pelleted, and resuspended in 2 × SDS sample buffer; one-third of the sample was heated for 10 min at 100 °C and subjected to SDS-polyacrylamide gel electrophoresis, followed by Western blotting with the ECL (Amersham Pharmacia Biotech) method. E1A monoclonal antibody, M73, was described previously (27). p53 monoclonal antibody (DO-1) and CBP polyclonal antibody were from Santa Cruz Biotechnology, Inc., Santa Cruz, CA.

    RESULTS AND DISCUSSION
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Abstract
Introduction
Procedures
Results & Discussion
References

We have analyzed the mechanism of transcriptional regulation of the human PCNA gene by p53 and adenoviral 12 S E1A proteins. Consistent with earlier reports (4, 5, 14, 15), E1A and p53 individually activated PCNA gene transcription (3- and 9-fold, respectively; Fig. 1A). This study is the first attempt to compare the mechanisms underlying the effect of these proteins acting individually as well as together on PCNA gene transcription. In previous studies, either E1A effects on PCNA gene transcription were examined in cell lines known not to contain much functional p53 protein or the effect of p53 on E1A function was not addressed (4, 5). Likewise, in studies where the effect of p53 on PCNA transcription was analyzed (14, 15), the effect of E1A on p53 function was not tested. Experiments using Saos-2 (p53-/-) cells and the PCNA gene promoter enabled us to analyze the transcriptional effects of these two proteins individually as well as in the presence of each other.

Role of CBP in Differential Effect of 12 S E1A on PCNA Transcription in Presence and Absence of p53-- Our experiments revealed that CBP is an essential component of both p53-mediated and 12 S E1A-mediated transcriptional activation of the PCNA promoter (Figs. 1-3). First, when wild type 12 S E1A was cotransfected with p53, transactivation by p53 was reduced about 3-fold. That the 12 S Delta 2-36 mutant, which is unable to interact with p300/CBP, failed to repress transcriptional activation by p53 (Fig. 1B) suggests that p300/CBP is involved in activation of the PCNA promoter by p53. This conclusion is further supported by the observation that another E1A mutant, 12 S YH47/928, deficient in interacting with members of the pRB protein family, did retain partial repression of activation by p53 (Fig. 1C). On the other hand, in the absence of p53, wild type 12 S E1A activated PCNA transcription, whereas 12 S E1A Delta 2-36 was not as effective (Fig. 1, A and B). 12 S E1A.FS, a control plasmid which does not produce any E1A protein because of a frameshift mutation, produced neither activation nor repression.2 When a plasmid expressing p53 with mutations in the amino-terminal transcriptional activation domain (p53-22/23) was transfected, there was no increase in PCNA transcription.2 To ensure that the repressive effect of 12 S E1A on p53-mediated transcriptional activation was not because of an effect of E1A on p53 protein expression, extracts from transfected cells were subjected to Western blot analysis using p53 and E1A antibodies. The results (Fig. 1, D-F) showed that p53 protein expression remains constant regardless of the presence of wild type or mutant E1A proteins. The ability of E1A to repress transcriptional activation of the PCNA promoter by p53 is consistent with earlier results obtained with other promoters (17-20). Second, increased expression of CBP by transfection could relieve 12 S E1A-mediated repression of PCNA transcriptional activation by p53 (Fig. 2B). Interestingly, however, increased amounts of CBP failed to fully restore transcriptional activation to the level elicited by p53 in the absence of E1A, suggesting that CBP may be functioning in concert with some other factor(s) in transcriptional activation by p53. High amounts of CBP caused only a modest increase in the already high PCNA transcriptional activation produced by p53. These results (Fig. 2A) demonstrated that although the amount of endogenous CBP in Saos-2 cells is sufficient for functioning as a coactivator for transcriptional activation by p53. The amount of endogenous CBP becomes limiting when p53 and 12 S E1A are present together (Fig. 2B). Third, when endogenous CBP was depleted by transfecting a CBP antisense construct, there was considerable dose-dependent reduction in transcriptional activation by p53 (Fig. 3A). Finally, transfection of antisense CBP plasmid suppressed p53-independent, 12 S E1A-dependent activation of PCNA transcription to the basal level (Fig. 3B) showing that CBP is an important component of 12 S E1A-mediated transcriptional activation of native PCNA promoter. This observation is consistent with an earlier report showing that GAL4-CBP, in the presence of 12 S E1A, activated a synthetic GAL4-PCNA promoter (25). When concentration of the antisense CBP construct, but not the control plasmid, was increased, CBP protein levels were considerably reduced (Fig. 3, C and D, compare lanes 5-8 with lane 1). Moreover, inhibition of the p53-mediated as well as the E1A-mediated transcriptional activation of the PCNA promoter coincided with the reduction in CBP protein levels (i.e. when 240 fmol or more of antisense CBP plasmid were transfected; Fig. 3, compare A and B with C), further demonstrating direct involvement of CBP in the transcriptional activation of the PCNA promoter by p53 as well as by 12 S E1A.


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Fig. 1.   Transcriptional regulation of PCNA gene promoter by p53 and 12 S E1A. A, effect of 12 S E1A wild-type on p53-dependent and -independent PCNA gene transcription. Increasing amounts of E1A wild type and native human PCNA promoter (-1265/+62) (1 µg) were transfected with or without p53 (1.25 ng) into 1.3 × 105 Saos-2 cells. Transcription in the absence (hatched bars) and presence (filled bars) of p53, measured as luciferase activity, are shown. B, effect of 12 S E1A Delta 2-36 mutant on p53-dependent and -independent PCNA gene transcription. C, effect of 12 S E1A YH47/928 mutant on p53-dependent and -independent PCNA gene transcription. The results are shown as bar graphs with mean ± S.D. from three independent transfections. D-F, total proteins from cell pellets corresponding to 1.3 × 105 cells transfected as in A, B, and C, were subjected to Western blotting with E1A (M73) monoclonal antibody (upper panel) and p53 monoclonal antibody (DO-1; Santa Cruz Biotechnology, Inc.) (lower panel).


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Fig. 2.   CBP can relieve E1A-mediated repression of PCNA transcriptional activation by p53. A, Saos-2 cells were transfected with wild type PCNA reporter plasmid (-1265/+62) (1 µg), along with increasing amounts (0, 12.5, 25, 50, 75, and 100 ng) of CBP expression plasmid with and without p53 expression plasmid (12.5 ng), as indicated. The luciferase assay results are shown as bar graphs with mean ± S.D. from three independent transfections. B, Saos-2 cells were transfected with wild type PCNA reporter plasmid (-1265/+62) (1 µg), along with various combinations of wild type p53 (1.25 ng), 12 S E1A (875 ng), and CBP (0, 12.5, or 50 ng) expression plasmids as shown at the bottom. The luciferase assay results are shown as bar graphs with mean ± S.D. from three independent transfections.


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Fig. 3.   CBP is essential for both p53-mediated and E1A-mediated transcriptional activation of PCNA promoter. A, effect of CBP antisense plasmid on transcriptional activation of PCNA gene by p53. Increasing amounts of antisense plasmid or equimolar amount of control vector plasmid pSRalpha were transfected into Saos-2 cells with or without cotransfected p53. Transfection was as described for Fig. 1. Transcriptional activity measured as luciferase activity is shown with mean ± S.D. from three independent transfections. open circle , CBP antisense; bullet , p53 + CBP antisense; square , vector; black-square, p53 + vector; B, effect of CBP antisense plasmid on transcriptional activation of PCNA gene by 12 S E1A. Experiments were as in A, except that 125 ng of 12 S E1A expression plasmid was transfected instead of p53 expression plasmid. open circle , CBP antisense; bullet , E1A wild type + CBP antisense; black-square, E1A wild type + vector. C and D, total proteins from cell pellets corresponding to 1.3 × 105 cells transfected with increasing amounts of CBP antisense expression plasmid (C) or control vector plasmid, pSRalpha (D), were subjected to Western blotting with CBP polyclonal antibody (A-22; Santa Cruz Biotechnology. Inc.).

Role of CRE in the Transcriptional Activation of PCNA by p53 and E1A-- p300/CBP can interact with certain members of the CREB/ATF and AP1 family of transcription factors, which bind to the CRE. Thus CRE can be a major "recruiter" of CBP to a gene promoter. We wanted to test whether the -53 GTGACGTCG -44 region in the PCNA promoter homologous to the CRE consensus 5'-GTGACGT(A/C)(A/G)-3' (28) is involved in transcriptional activation by p53. The PCNA promoter region containing the wild type CRE, but not the mutant site -53 tTGgatcCG -44, is capable of specifically binding CREB-1 and ATF-12 and thereby recruiting CBP to the PCNA promoter (25). We analyzed the transcriptional response of wild type and CRE mutant (-53 tTGgatcCG -44) PCNA promoters to p53 as well as to E1A. The results shown in Fig. 4 have demonstrated for the first time that CRE, which recruits CBP to the PCNA core promoter, synergizes with p53 to activate transcription (Fig. 4). CRE is a core PCNA promoter element, because mutation of this element severely debilitates (about 7-fold) the basal transcription of the promoter. Our results are consistent with the reported importance of this element for PCNA basal transcription as well as for full activation by 12 S E1A (29); however, it is clear that this element is not uniquely required for activation by E1A, but is also important for transcriptional activation by cellular p53. Indeed, the effect of CRE and p53 in transcriptional activation of the PCNA promoter is synergistic, whereas the effect of CRE and 12 S E1A on PCNA transcription appears to be additive. Therefore, regulation of PCNA transcription by p53 is intimately linked to the basal transcription machinery by the core promoter CRE. These results suggest that the role of CRE may not be the same for p53-mediated as for E1A-mediated transcriptional regulation of the PCNA gene. Future studies should reveal the specific CRE-binding factors responsible for these effects.


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Fig. 4.   CRE in the PCNA core promoter synergizes with p53 to activate transcription. The PCNA reporter plasmids are shown at the top. Saos-2 cells were transfected as in Fig. 1 except that 875 ng of wild type 12 S E1A was transfected. The combination of transfected plasmids and -fold transcriptional activation are shown at the bottom. The luciferase assay results are shown as bar graphs with mean ± S.D. from three independent transfections.

How does E1A target CBP to activate transcription, while at the same time targeting it to repress activation of the same promoter by p53? We propose a working model (Fig. 5) where, in the absence of cellular p53 or viral E1A, the PCNA promoter is transcriptionally weak. Interaction of p53 with CBP causes a change in the conformation of these proteins and/or another associated cellular factor(s) (named `X' in Fig. 5), which, in turn, results in strong transcriptional activation. 12 S E1A can also associate with CBP, leading to a relatively weak activation of transcription. In the presence of p53, 12 S E1A efficiently disrupts CBP-p53 association, resulting in repression of p53-mediated transcriptional activation. The transcriptional activation of the PCNA promoter caused by 12 S E1A is consistently lower than that elicited by p53 (Figs. 1A and 2B). Moreover, increased expression of CBP can only partially relieve repression of p53-mediated activation by 12 S E1A (Fig. 2B). These results suggest that E1A may target, besides CBP, another factor required for transcriptional regulation by p53. Results with the core promoter CRE described here as well as ongoing experiments suggest that the factor(s) involved may be assembled on the core promoter region of the PCNA gene. Core promoter regions of various genes are known to be important determinants of activator function (30-33) and promoter selective transcription of certain cell cycle and growth control genes (34).


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Fig. 5.   Working model for the role of CBP in transcriptional regulation of the PCNA gene. The PCNA promoter with the p53 binding site (open box) is represented by a curved line. X represents an unknown cellular factor(s). In the absence of p53 or E1A, PCNA transcription is weak (thin arrow). Interaction of the promoter-bound p53 with CBP results in an active p53-CBP-X complex, which, in turn, interacts with the basal transcription machinery leading to strong transcriptional activation. When E1A is present, it disrupts the p53-CBP interaction repressing the transcriptional enhancement caused by p53. Regardless of p53, E1A can interact with CBP and/or with X, which leads to modest transcriptional activation. The net effect is E1A taking over the transcriptional control of PCNA from the effects of normal signal transduction mediated by the p53 pathway.

Whatever the nature of the factor(s) involved, the results presented here demonstrate the dual effect of 12 S E1A on the same target gene, resulting in low level activation of PCNA transcription, while abrogating higher levels of p53-dependent transcriptional activation. Thus, disruption of p53 transcriptional function would enable 12 S E1A to unlink transcription of the PCNA gene from normal cellular signal transduction. It is likely that higher levels of PCNA and p21 produced as a result of transcriptional activation by p53 shift the balance toward cell cycle arrest and potential for DNA repair rather than DNA replication. 12 S E1A may counteract the cell cycle arrest by repressing p53-mediated transcriptional activation, while simultaneously activating PCNA transcription to a level sufficient for DNA replication.

    ACKNOWLEDGEMENTS

We thank J. Atencio for excellent technical assistance. We are thankful to R. Goodman (RSV-CBP), S. Ishii (pSRalpha -anti CBP and pSRalpha ), A. Levine (CMV-p53 wt and CMV-p53/22, 23 mut), and G. Morris (-1265 PCNA) for clones; and E. Harlow for the E1A antibody (M73). We thank Phil Tucker for discussions and N. Elango for providing access to the luminometer.

    FOOTNOTES

* This work was supported in part by American Cancer Society Institutional Grant IRG-116RAC from the University of Texas Health Science Center at San Antonio and NCI Cancer Center Support Grant P30 CA54174 from the San Antonio Cancer Institute.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

parallel To whom correspondence should be addressed: Cancer Therapy & Research Center, Gene Regulation Laboratory, 8122 Datapoint Dr., Suite 700, San Antonio, TX 78229. Tel.: 210-616-5876; Fax: 210-692-7502.

1 The abbreviations used are: PCNA, proliferating cell nuclear antigen; CRE, cyclic AMP response element; CREB, CRE-binding protein; CBP, CREB-binding protein.

2 S. Karuppayil and G. Das, unpublished observations.

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Abstract
Introduction
Procedures
Results & Discussion
References

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