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Advances in Brief |
Departments of Clinical Oncology [A. S., S. K., R. K., C. I.] and Cell Biology [K. E., M. Os., M. Ob., S. I.], Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575; Department of Retroviral Regulation, Tokyo Medical and Dental University, Medical Research Division, Tokyo 113-8519 [Y. I.]; and Nara Institute of Science and Technology, Nara 630-01 [K. K.], Japan
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ABSTRACT |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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The p53 genes are highly conserved in lower species (such as squid) and higher mammals, and for a long time, it was thought there was no p53 family (6)
. The first mammalian p53 homologue to be identified was rat Ket (7)
, after which it was considered likely there would be human p53 homologues. Two human p53 homologues, p73 and p51/p63 (hereafter referred to as p51), were identified by a degenerate PCR method (8
, 9)
, and subsequently, they were also identified in other laboratories (10, 11, 12, 13)
. The predicted protein structures of the two human homologues are similar to that of human p53 protein, and 
60% of their amino acids in the region corresponding to the p53 DNA-binding domain are identical to those of p53 (8
, 9)
. In contrast, only 30% of the amino acids of the NH2- and COOH-terminal portions of the homologues are identical to those of p53 protein (8
, 9)
, although the COOH-terminal oligomerization domain is relatively well conserved among human p53, p73, and p51 and squid p53 (8
, 9 , 14)
. The NH2- and COOH-terminal portions of p53 encode the regulatory domains of p53 that are involved in p53 activation by the upstream signal (15, 16, 17, 18)
. In 1997, the upstream biological signal that activates p73 was shown to be different from the signal that activates p53 (7
, 8)
. On the basis of these observations, we predict that the upstream signals of p51 and p53 are also different and that p53 and its homologues partially or exclusively share downstream target genes and, therefore, both play roles in biological events such as G1 arrest and apoptosis. In fact, initial studies showed that both p73 and p51 proteins, when overexpressed in human cells, can up-regulate p21/WAF1 transcription and induce apoptosis (9
, 19)
. Furthermore, initial mutation screening of p73 and p51 in a variety of human tumors (9
, 20, 21, 22, 23)
and cell lines (9)
revealed rare mutations in the open reading frames. All the evidence to date suggests that the p53 homologues show functional similarities and differences.
In view of the structural and functional similarities of p51 and p53, it is obviously important to study the biological pathway through p51 that contains unknown upstream and downstream signals and compare this pathway with the known p53 pathway. In this study, we used both yeast and mammalian cell systems to examine the ability of p51 to trans-activate p53-inducible promoters other than the p21/WAF1 promoter, i.e., BAX, MDM2, and 14-3-3
promoters.
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Materials and Methods |
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(EMBL accession no. AF029081, nucleotides 6017–6797) genes, respectively. All these fragments contain the p53RE(s), as shown in Fig. 1
. These low-copy centromeric vectors are maintained stably in yeast grown on medium lacking tryptophan and express the yeast HIS3 gene, depending on the wild-type p53 expression.
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B, a plasmid identical to pRS424 (26)
, except that the BamHI site had been disrupted by the Klenow enzyme, producing pAS01. A BamHI PCR fragment of GFP cDNA (codon 2, termination codon) derived from pQB2 (27)
was inserted into the BamHI sites of the HIS3 gene of pAS01, which was prepared using an inverse PCR technique, generating pAS01G. Then, the EcoRI fragments containing the p53RE from pCI-WAFP(HIS), pCI-MDMPs(HIS), pCI-BAXPs(HIS), and pCI-SIGMAPs(HIS) were inserted into the EcoRI site of pAS01G, generating pAS03G, pAS05G, pAS07G, and pAS09G, respectively. These high-copy 2µ vectors are maintained stably in yeast grown on medium lacking tryptophan and express GFP, depending on the wild-type p53 expression. The GFP protein thus produced is a variant form, with S65T and S147P mutations (27)
, and emits a stronger fluorescent signal than wild-type GFP and variant GFP with only the S65T mutation.
For the luciferase assay, the p53 expression vector p53/CMV and p51A expression vector p51/CMV-2 were constructed by inserting the BamHI/EagI fragments derived from the pLSC53A- and pCIP51-2-containing open reading frames of p53 cDNA and p51A cDNA, respectively, into pcDNA1.1/Amp (Invitrogen, Carlsbad, CA) with the 3' untranslated region of the p53 gene. We also constructed the HA-tagged p53 expression vector pHA53/CMV and HA-tagged p51A expression vector pHA51/CMV-2 by replacing the p53 and p51A sequences of p53/CMV and p51/CMV-2 with HindIII fragments containing HA-tagged p53 and HA-tagged p51A sequences, respectively. These vectors were used for both the luciferase and immunoblotting assays. Firefly luciferase reporter plasmids were constructed as follows. A double-strand linker containing the SpeI-EcoRI-SacII-PstI sequence was inserted into the BglII sites of pGL3-Basic and pGL3-Promoter (Promega, Madison, WI), generating pGL3E-Basic and pGL3E-Promoter, respectively. The EcoRI fragments derived from pCI-WAFP(HIS), pCI-MDMPs(HIS), pCI-BAXPs(HIS), and pCI-SIGMAPs(HIS) were inserted into the EcoRI site of pGL3E-promoter, generating p21Ps luc, pMDMPs luc, pBAXPs luc, and pSIGMAPs luc, respectively. The p21Luc-1 plasmid was constructed by inserting the HindIII fragment containing the p21/WAF1 promoter (GenBank accession no. U24170, nucleotides 2256–4594) into the HindIII site of pGL3-Basic, and pMDMPl luc, BAXP12 luc, and pSIGMAP1 were constructed by inserting the EcoRI fragment containing the promoters of the MDM2 (GenBank accession no. U28935, nucleotides 314–982), BAX (GenBank accession no. U17193, nucleotides 288–646), and 14-3-3 (EMBL accession no. AF029081, nucleotides 6040–8610) genes, respectively, into pGL3E-Basic. The promoter sequences of p21Luc-1, pMDMPl luc, pBAXP12 luc, and pSIGMAP1 luc each contain a p53RE, TATA box, and transcription initiation sites. The promoter sequences inserted into all the reporter plasmids were obtained by subjecting normal genomic DNA to the PCR using a set of appropriate primers, except for the p21/WAF1 promoter sequences, which were derived from pWWP-CAT (a gift from Bert Vogelstein, Johns Hopkins University, Baltimore, MD). The Renilla luciferase expression vector pRL-CMV (Promega) was used as an internal control to correct values according to the transfection efficiency of the dual luciferase assay.
Yeast Strains and Media.
Basic yeast manipulation was carried out as described previously (28)
. The three haploid yeast strains used for the p53 and p51A transcription assays were ySS5 (MATa, ura3-1, ade2-1, trp1-1, his3-11, leu2-3, 112, can1-100, pep4::BURA3, pSS1; Ref. 25
), YSIS (MATa, ura3-1, ade2-1, trp1-1, his3-11, leu2-3, 112, can1-100, pep4::BURA3; Ref. 29
), and YPH499 (MATa, his3200, ade2-101, leu21, ura3-52, trp1-289, lys2-801; Stratagene, La Jolla, CA). Frozen competent yeast cells were prepared as described previously (30)
, and the solid media used for prototrophic selection of appropriate plasmids and the His phenotype assay were the synthetic complete media lacking leucine and tryptophan (SC -leu -trp) and lacking histidine (SC -his -leu -trp), respectively, as described previously (25)
.
Yeast-based Transcription Assay.
The HIS3 transcription assay described previously (25)
was used. Briefly, cells of the strain YSIS containing the p53-inducible HIS3 reporter plasmid were transformed with the p53 or p51A expression vector on SC -leu -trp, and the resulting transformants were assayed for histidine prototrophy (His phenotype) on SC -his -leu -trp plates. For the GFP reporter assay, cells of the strains YSIS and YPH499 were cotransformed with the p53 or p51A expression vector and a GFP reporter plasmid (see above). The resulting colonies on SC -leu -trp were assayed directly for GFP expression using a fluorescence microscope (MZ8; Leica) equipped with a GFP Plus filter.
Quantification of the Fluorescent Signal of GFP.
The fluorescence intensities of GFP were determined by analyzing, using a fluoroscanmeter (Fluoroskan Ascent FL, Dainippon, Tokyo, Japan), living yeast cells on 96-well microtiter plates containing SC -leu -trp medium.
Cell Lines and Transfection.
The p53-null human osteosarcoma cell line Saos-2 and the p53-deficient lung cancer cell line EBC-1 were obtained from the American Type Culture Collection (Manassas, VA) and the Japanese Cancer Research Resource Bank, respectively, and grown in 12-well tissue culture plates containing RPMI 1640 supplemented with 10% (v/v) heat-inactivated fetal bovine serum at 37°C in the presence of 5% CO2. Transient transfections were performed using the Effectene (Qiagen, Hilden, Germany) transfection reagent. For the luciferase assay, Saos-2 and EBC-1 cells grown to 70% confluence in 12-well culture plates were cotransfected with the p53 or p51A expression vector (15 or 150 ng) and the p53-responsive luciferase reporter plasmid (0.4 µg) as well as pRL-CMV (0.4 µg) and incubated for a further 24–48 h. For immunoprecipitation, 4.5 µg of the required expression vector were transfected into Saos-2 cells grown in tissue culture dishes (60 x 15 mm) and incubated for a further 36 h.
Luciferase Assay.
The activities of Firefly luciferase expressed by the p53-responsive reporter plasmids were measured using the Dual-Luciferase reporter assay system (Promega) and a Fluoroskan Ascent FL (Dainippon) and corrected according to the Renilla luciferase activities derived from pRL-CMV for assessment of the transfection efficiency. The relative luciferase activity was calculated using the formula: (Firefly luciferase activity)/(Renilla luciferase activity).
Immunoprecipitation and Immunoblotting.
Yeast and Saos-2 cell lysates were prepared as described previously (31
, 32)
. To detect HA-tagged p53 and p51A proteins in Saos-2 cells, the lysates were immunoprecipitated with a rat high-affinity anti-HA monoclonal antibody (Boehringer Mannheim, Indianapolis, IN), fractionated by SDS-PAGE, and transferred electrophoretically to an Immobilon SQ filter (Millipore, Bedford, MA). The HA-tagged proteins were detected using the same antibody. The yeast lysates were fractionated directly by SDS-PAGE and transferred to the same membrane, and the HA-tagged p53 or p51A were detected using a mouse anti-HA monoclonal antibody (Boehringer Mannheim). The HA-tagged proteins were visualized using an enhanced chemiluminescence kit (Amersham Life Science, Buckinghamshire, United Kingdom).
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Results |
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. The p51 gene has two major splicing variants, p51A (also called p63
) and p51B (p63
), which are similar to the two major splicing variants of p73, p73ß, and p73, respectively (9)
. We chose p51A cDNA to be representative of p51 because this form possesses the strongest transactivation activity of the reported splicing variants of p51 (12)
. The basic structures of the p51 expression vectors with and without the HA sequence are identical to those of p53 in both yeast and mammalian expression systems (Fig. 1, A and B)
. To determine whether these vectors expressed p51 and p53 proteins, we transformed the p51 and p53 yeast expression vectors with HA sequences in YSIS yeast cells and subjected the cell lysates to immunoblotting with an anti-HA antibody. As shown in Fig. 2 A
, both HA-tagged p51 and HA-tagged p53 proteins in the yeast cells were detected clearly, and their levels were comparable, although the level of p51 was significantly lower than that of p53. We also examined the expression of these proteins in Saos-2 cells subjected to transient transfection with the HA-tagged p51 or p53 expression vector. The cell lysates were immunoprecipitated and immunoblotted with an anti-HA antibody and, as shown in Fig. 2B
, p51 protein was detected clearly, although its level was significantly lower than that of p53 protein. Although the different protein levels may have been attributable to differences in antibody accessibility, the transcription/translation efficiency of the reporter genes and/or posttranslational events between p51 and p53, we did not pursue this issue in this study. We observed that the electrophoretic mobilities of p51 from both yeast and Saos-2 cells on a SDS-polyacrylamide gel were lower than those of p53 and that Saos-2 cells yielded two separate p51 bands (Mr 60,000 and 66,000).
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(Fig. 1A)
genes previously identified as p53 target genes into the upstream region of the GAL1 minimal promoter lacking the upstream activating sequences of the HIS3 or GFP reporters used for the yeast assay. Identical fragments were also introduced into the enhancerless SV40 promoter of the luciferase reporters for mammalian cells ("enhancer reporters"). We also constructed a series of reporter plasmids with promoter sequences containing transcription initiation sites as well as the p53-binding sequences by inserting the fragments into promoterless/enhancerless luciferase reporter plasmids ("promoter reporters").
In Yeast, p51 Acts as a Transcriptional Activator through a p53-binding Sequence.
In a previous study, we showed that the sequence-specific transcriptional activity of p53 can be monitored by a simple yeast growth assay (25)
. Therefore, to examine whether p51 can regulate the p53 target promoters p21/WAF1, MDM2, BAX, and 14-3-3, we used a similar yeast system. The p51 and p53 expression vectors were cotransformed with a series of HIS3 reporter plasmids (see above) as well as an artificial p53-responsive sequence, RGC (pSS1; Ref. 25
), and the growth of the resulting transformants on plates lacking histidine was assayed to determine the His phenotype. As shown in Table 1
, all the transformants harboring p51 or p53 showed the His+ phenotype to varying degrees, indicating that p51 also acts as a sequence-specific transcriptional activator in yeast through the previously reported p53REs.
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with either the p53 or p51 expression vector. The fluorescence intensities of the resulting transformants were analyzed at 37°C, the physiological temperature for human proteins, and 30°C, the temperature that may alter the conformations of human proteins expressed in yeast (Fig. 3)
. As expected, at 37°C (Fig. 3, A and B)
, p53 activated all four p53 target promoters tested in this study, whereas p51 activated only three of the four promoters, as follows. The MDM2 reporter that was activated strongly by p53 was also activated strongly by p51, the BAX reporter that was activated moderately by p53 was activated strongly by p51, the p21/WAF1 reporter that was activated moderately by p53 was activated weakly by p51, and the 14-3-3 reporter that was activated moderately by p53 was not activated significantly by p51. At 30°C (Fig. 3, C and D)
, significant reductions of the fluorescence intensity relative to that at 37°C were observed only in cultures that expressed p53 with the BAX reporter (76% reduction) and the 14-3-3 reporter (77% reduction), whereas no significant changes in GFP expression levels occurred in cultures expressed p51 (Fig. 3D)
. These results suggest that the conformations of the DNA-binding domains of p51 and p53 that bind to each p53RE differ slightly. Similar results were observed when HA-tagged p53 and p51 and a different yeast strain (YPH499) were used (data not shown).
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. We used a series of promoter reporters and found that p51 significantly activated the p21/WAF1, MDM2, and BAX promoters but not the 14-3-3 promoter. Similar results were obtained when we used a series of enhancer reporters (Fig. 4A)
. These results indicate that p51 has the ability to activate p21/WAF1, MDM2, and BAX through the known p53-binding sequences within the promoters. Similar results were obtained when we subjected human lung cancer EBC-1 cells (Fig. 4B)
to the enhancer reporter assay. The levels of luciferase activity induced by p51 were significantly lower than those induced by p53 with all the reporters tested except the BAX reporter. However, we cannot conclude that the transcriptional activity of p51 was lower than that of p53 because the expression level of the p51 protein in Saos-2 cells was lower than that of p53 (Fig. 2)
and because our experiments involved overexpression, which means that the data may not reflect physiological conditions. Even so, the BAX promoter in both cell lines was activated by p51 at levels comparable with those of p53. We confirmed these observations in experiments using different incubation times (36 and 48 h) for transfection, higher levels (10-fold) of the expression vector DNAs and HA-tagged p51 and p53 expression vectors (data not shown). These results suggest strongly that the abilities of p51 and p53 to transactivate distinct p53-responsive promoters differ.
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Discussion |
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Recently, two independent groups reported that p73, another p53 homologue, also trans-activated differentially distinct p53 target genes. Di Como et al. (33)
carried out yeast and mammalian transcription assays and showed that p73 up-regulated the BAX promoter as efficiently as it did p53, but up-regulated the p21/WAF1 and MDM2 promoters less efficiently than it did p53. Their results are similar to the data we obtained in this study. This is not surprising because p51 and p73 are the structurally closest relatives of the p53 homologues: the homologies of the DNA-binding domains of p51 and p73, p51 and p53, and p73 and p53 are 87, 60, and 63%, respectively. Furthermore, Zhu et al. (34)
showed that tetracycline-regulated p73 expression in a lung cancer cell line activated differentially endogenous p53 target genes. Among these genes, p73 activated efficiently a subset of the genes, including 14-3-3, which was not activated significantly in our study. Although the methods used were different, it is likely there are differences between p51- and p73-mediated trans-activation of distinct p53 target genes. In the light of these observations, we predict that the two p53 homologues partially but not exclusively share downstream p53 target genes and, therefore, differentially regulate the cell cycle and apoptosis in response to currently unknown upstream signals. Alternatively, not all the genes reported as p53 targets are functionally relevant to p53 under physiological conditions, and some of these and also some currently unidentified genes may be specific targets of p51 and/or p73. To explore these possibilities, it is obviously important to study both the upstream and downstream signals of p51 and p73.
Finally, it would be interesting to elucidate whether p53 homologues are involved in human tumorigenesis. In previous studies, we and others demonstrated that germ-line and somatic mutations in p53 could be screened efficiently by performing yeast-based functional assays (25 , 35 , 36) . The yeast assay we carried out in this study has technical advantages over the previous versions, namely the use of GFP as a reporter gene, which enables more rapid and quantitative analyses and, therefore, simplifies the detection of functionally subtle mutations, and the multiple reporter systems for p53 target genes, which enables the mutations to be characterized. Although there are many possible applications of this assay for both basic and clinical studies of p53 and its homologues, currently we are using it for the detection and functional evaluation of tumor-derived missense mutations in p51.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture and the Ministry of Health and Welfare. 
2 To whom requests for reprints should be addressed, at Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Phone: 81-22-717-8547; Fax: 81-22-717-8548; E-mail: chikashi{at}idac.tohoku.ac.jp
3 The abbreviations used are: p53RE, p53-responsive cis-acting element; HA, hemagglutinin; RGC, ribosomal gene cluster; GFP, green fluorescent protein.
Received 3/18/99. Accepted 4/29/99.
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