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[Cancer Research 59, 2810-2814, June 15, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Identification of a Transactivation Activity in the COOH-Terminal Region of p73 Which Is Impaired in the Naturally Occurring Mutants Found inHuman Neuroblastomas1

Naoyuki Takada, Toshinori Ozaki, Shingo Ichimiya, Satoru Todo and Akira Nakagawara2

Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717 [N. T., T. O., S. I., A. N.]; Department of Pathology, Sapporo Medical College, Sapporo 060-8556 [S. I.]; and First Department of Surgery, Hokkaido University School of Medicine, Sapporo 060-8638 [N. T., S. T.], Japan


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
p73 is a recently cloned tumor suppressor gene that is highly homologous to p53, and the products of both possess similar functions in inhibiting cell growth and inducing apoptosis. Interestingly, the COOH-terminal region of p53 displays no significant homology with that of p73. Moreover, p73 has an additional segment at its COOH terminus. Recently, we have found two mutations of p73 with amino acid substitution (P405R and P425L) in primary neuroblastomas. Because the region (amino acid residues 382–491) contains a glutamine- and proline-rich domain, we hypothesized that it has a transactivation function, and the mutations found in tumors result in loss of function. To test it, we used the yeast GAL4 DNA-binding fusion system. Yeast transformants expressing a GAL4-p73(1–112) or a GAL4-p73{alpha}(380–513) fusion protein were grown in SD medium lacking histidine and tryptophan and exhibited a significant induction of ß-galactosidase activity. Transient transfection experiments revealed that both of fusion proteins could induce the chloramphenicol acetyltransferase activity in mammalian cells, indicating that the COOH-terminal as well as NH2-terminal regions of p73 had significantly high levels of transactivation activity. Furthermore, the former activity was severely impaired in two naturally occurring mutant forms found in neuroblastomas. These suggest that, unlike p53, p73 has two domains with transactivation function, one in the NH2-terminal region and the other in the COOH-terminal region. Loss of function mutation in the latter might be involved in tumorigenesis and/or tumor progression.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
p53 is one of the most frequently inactivated genes in human tumors (1, 2, 3, 4) , and it encodes a nuclear phosphoprotein with a function of checkpoint control to regulate the entry from G1 into the S phase of the cell cycle progression (5) . In response to various types of cellular stresses such as DNA damage and hypoxia, p53 suppresses cell growth and triggers apoptosis (6, 7, 8) . One of the ways by which p53 exerts its antiproliferative activity is mediated by its sequence-specific DNA-binding ability and transcriptional transactivation function (9, 10, 11) . To date, a number of putative p53 target genes have been identified, including GADD45, mdm2, p21Waf1, cyclin G, and Wig-1 (12, 13, 14, 15, 16, 17, 18) . There are four functional domains in the p53 protein. The highly acidic transactivation domain and the sequence-specific DNA-binding domain are located at the NH2 terminus (residues 1–42) and the middle region (residues 102–292), respectively (8 , 19) . The oligomerization domain consists of 41 COOH-terminal amino acids (residues 324–355), and the nonspecific DNA-binding region is located at the COOH terminus (residues 368–393). Most of the p53 mutations found in various tumors are localized in the highly conserved DNA-binding domain and cause a loss of DNA-binding activity and transactivation function (4 , 19) . Interestingly, Gu and Roeder (20) have demonstrated that the COOH-terminal region of p53 could be acetylated by p300, and its modification enhances the sequence-specific DNA-binding activity.

Recently, Kaghad et al. (21) have unexpectedly discovered a new gene, termed p73, which encodes a nuclear protein with a significant homology to p53. Indeed, the NH2-terminal transactivation domain, the sequence-specific DNA-binding region and the oligomerization region are remarkably conserved between them. Intriguingly, there exist two p73 isoforms (p73{alpha} and p73ß) generated by alternative splicing, and they contain different COOH termini (21) . Jost et al. (22) have demonstrated that the expression of reporters carrying a p53-responsive element is induced by the ectopic overproduction of p73{alpha} or p73ß, indicating that p73 might recognize the p53 target site and possess a transactivation ability. In support of this observation, transient expression of the exogenous p73{alpha} induces the expression of p21Waf1 (21) . Stable overproduction of p73 protein inhibits the colony formation of neuroblastoma (SK-N-AS) or osteosarcoma (SaOS-2) cell line (21 , 22) . p73 also induces apoptosis when it is transduced into certain cell lines such as baby hamster kidney cells (22) . Thus, p73 seems to possess molecular properties and biological functions that are similar to those of p53.

However, the COOH-terminal region of p73 exhibits no significant sequence homology with that of p53. In addition, p73 contains an extra sequence (216 and 79 amino acids for p73{alpha} and p73ß, respectively) at its COOH terminus (21) . To date, no function has been ascribed to this COOH-terminal region of p73. In this study, we have found that the COOH-terminal portion of p73 (residues 380–513) and the NH2-terminal region of p73 (residues 1–112) act as transcriptional transactivators when they are fused to the GAL4 DNA-binding domain, and the former activity is significantly abolished by two different missense mutations that we have found in primary neuroblastomas (23) .


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Cell Culture.
COS and HeLa cells were cultured at 37°C in DMEM supplemented with 10% heat-inactivated fetal bovine serum and kanamycin.

Plasmid Construction.
DNA fragments encoding the COOH-terminal regions of wild-type (residues 380–513 or 499–636) and mutant forms (P405R and P425L) of p73{alpha} were amplified by RT-PCR using total RNA derived from normal breast tissues and two independent neuroblastoma tissues (23) as templates, respectively.

The following oligonucleotide primers were used for the PCR-based amplification: 5'-GTCGAATTCTTGGTGCCGCAGCCACTGGTG-3' and 5'-GTCGGATCCCCCTTGGGAGGTGAAATACTC-3' for the generation of p73{alpha}(380–513) and 5'-GTCGAATTCGGATTGGGGTGTCCAAACTGC-3' and 5'-GTCGGATCCTCAGTGGATCTCGGCCTCCG-3' for the production of p73{alpha}(499–636). PCR products were gel-purified, digested with EcoRI/BamHI, and inserted into the EcoRI and BamHI site of the yeast expression vector pGBT9 or mammalian expression vector pM (Clontech, Palo Alto, CA). In each case, DNA fragment was ligated in-frame to the GAL4 DNA-binding domain.

Yeast Strain and Transformation.
The yeast reporter host strain HF7c was obtained from Clontech. Cells were grown in YPD (1% yeast extract, 2% peptone, and 2% glucose) or in the SD synthetic medium (0.67% yeast nitrogen base and 2% glucose with appropriate amino acids). Competent HF7c cells were transformed with the pGBT9 derivatives encoding various GAL4 DNA-binding domain-p73{alpha} fusion proteins according to the manufacturer’s instructions and grown on the solid SD agar medium lacking tryptophan or tryptophan and histidine. ß-Galactosidase activity of the yeast transformants was measured according to the manufacturer’s instructions (Clontech). Briefly, transformants were grown in SD medium lacking tryptophan, harvested, and lysed by freeze and thaw procedure. Cell lysates were incubated in Z buffer (60 mM Na2HPO4, 40 mM NaH2PO4, 10 mM KCl, and 1 mM MgSO4) containing ß-mercaptoethanol and o-nitrophenylgalactoside at 30°C for 4 h. The reaction was stopped by the addition of 1 M Na2CO3, and absorbances at 420 nm were measured.

Growth Curves.
HF7c transformants carrying various pGBT9 constructs were maintained in SD medium lacking tryptophan and histidine. Cultures were grown at 30°C with vigorous shaking, and the absorbance at 600 nm was measured at different time intervals (24) .

ß-Galactosidase and CAT3 Assays.
COS or HeLa cells were cotransfected with 10 µg of each expression plasmid encoding various GAL4 DNA-binding domain-p73{alpha} fusion proteins plus the reporter plasmid pG5CAT (Clontech), which carries five consensus GAL4 recognition sites and an adenovirus E1b minimal promoter upstream of the CAT gene, and pCH110 (Amersham Pharmacia Biotech, Buckinghamshire, United Kingdom), which contains the bacterial lacZ gene under the control of SV40 early promoter by a Lipofectin method (Life Technologies, Inc., Gaithersburg, MD). Forty-eight h after transfection, cells were harvested and lysed by freeze and thaw procedure. Then, cell extracts were assayed for ß-galactosidase and CAT activities, as described previously (25) .


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
The COOH-Terminal Region of p73{alpha}(380–513) Induces a ß-Galactosidase Activity in Yeast Cells.
As described previously, p73 contains an additional sequence (216 residues for p73{alpha} and 79 residues for p73ß) at its COOH terminus compared with that of p53 (21) . Although the functional significance of the extra sequences in both isoforms remains to be unknown, we have noticed the presence of two short sequences within those additional segments, a glutamine- and proline-rich region (residues 382–413) and a proline-rich region (residues 425–491), both of which are shared in p73{alpha} and p73ß (Fig. 1)Citation . Because the recent studies suggest that the glutamine- and/or proline-rich sequences, along with a highly acidic domain, are often found in the activation domains of various transcription factors and play an important role in regulating transcription by RNA polymerase II (26, 27, 28) , we examined whether or not the COOH-terminal region of p73 possesses a transactivation function by using a yeast GAL4 DNA-binding fusion system. The GAL4 DNA-binding domain was fused with p73 fragment corresponding to the amino acid residues 380–513, 499–636, or 1–112. p73{alpha}(499–636) lacks the glutamine- and proline-rich sequence, whereas p73(1–112) contains an NH2-terminal acidic region, which is homologous with the activation domain of p53. Each of these expression plasmids was introduced into the yeast reporter host strain HF7c and the ability to activate the reporter genes was examined. The GAL4-p53(1–100) was used as a positive control. As shown in Fig. 2Citation , yeast transformants expressing p73{alpha}(380–513), p73(1–112), or p53(1–100) were able to grow in liquid medium lacking tryptophan and histidine, suggesting that these fusion proteins can activate transcription of the HIS3 reporter gene. However, transformants expressing GAL4 alone or p73{alpha}(499–636) could not grow without tryptophan and histidine. Basically, the similar results were obtained in the ß-galactosidase assays. As shown in Fig. 3Citation , yeast transformants carrying the empty vector or the expression plasmid encoding p73{alpha}(499–636) did not show ß-galactosidase activity, whereas a remarkable induction of ß-galactosidase activity was detected in the yeast transformants expressing p73(1–112) or p53(1–100), indicating that the NH2-terminal region of p73 possesses a transactivation ability, and its activity was as strong as that of p53. Interestingly, transformants expressing p73{alpha}(380–513) exhibited significantly high levels of ß-galactosidase activity, although the level was lower than those of p73(1–112) and p53(1–100).



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  		Fig. 1. Alignment of amino acid sequences of the COOH-terminal regions of p53, p73{alpha}, and p73ß. The sequence information was obtained from the GenBank database (p53, accession nos. X02469 and M60950; and p73, accession no. AB010153). , two glutamine- and/or proline-rich regions of p73{alpha} and p73ß; arrows, positions of amino acid substitutions found in two independent neuroblastomas. *, amino acids conserved between p53 and p73.

 


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  		Fig. 2. Histidine-independent growth of yeast transformants. Growth curves of Saccharomyces cerevisiae (HF7c) carrying pGBT9 derivatives that express the following GAL4 fusion proteins grown in medium lacking histidine and tryptophan: p53(1–100), p73(1–112), p73{alpha}(380–513), p73{alpha}(499–636), and pGBT9 alone (GAL4). Data points, representative results from three similar experiments; bars, SD. A600 nm of the cultures (Y axis) is plotted against time in culture (X axis).

 


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  		Fig. 3. ß-Galactosidase activity of yeast transformants. Miller units of the yeast transformants that express the GAL4-p53, GAL4-p73(1–112), GAL4-p73{alpha}(380–513), GAL4-p73{alpha}(499–636), or GAL4 alone were measured. Experiments were repeated three times Columns, means; bars, SD.

 
Transactivation Function of the COOH-Terminal Region of p73 in Mammalian Cells.
We further examined the transactivation ability of the COOH-terminal region of p73 in mammalian cells. To construct chimeric plasmids, we have used a mammalian expression vector pM, which contains a GAL4 DNA-binding domain under the control of SV40 promoter and pG5CAT, which possesses CAT as a reporter under the control of GAL4-responsive elements. pM-VP16, which expressed a GAL4 DNA-binding domain-VP16 fusion protein, was used as a positive control. The chimeric plasmids pM-VP16, pM-p73{alpha}(380–513), and pM-p73(1–112) were cotransfected into COS cells, together with the reporter plasmid pG5CAT which contained five GAL4 binding sites and an upstream activating sequence linked to the CAT gene. As shown in Fig. 4Citation , the p73{alpha}(380–513) fragment showed a significant transcription activation of the reporter when it was fused to the GAL4 DNA-binding domain, suggesting that the COOH-terminal region of p73 exhibited the transactivation function in mammalian cells. The strong transactivation ability has also been detected in the NH2-terminal region of p73. These observations were the same as those obtained in the yeast system, and similar results were also obtained in HeLa cells (data not shown).



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  		Fig. 4. Transcription activation by the COOH-terminal region of p73{alpha} in mammalian cells. A, COS cells were transfected with pM (negative control), pM-VP16 (positive control), pM-p73(1–112), or pM-p73{alpha}(380–513) along with the CAT reporter plasmid, pG5CAT, and the CAT activity of each transfection was determined by TLC. The data shown are the representative of three experiments. B, CAT activity of each construct is shown as a relative value when the CAT conversion activity of VP16 is set at 100%. Columns, means (n = 3); bars, SD.

 
Two Missense Mutations Cause a Significant Reduction of the Transactivation Ability Detected in the COOH-Terminal Region of p73.
Previously, we have found two kinds of missense mutation of p73 in two independent primary neuroblastomas (23) . In each case, proline residue was exchanged to arginine or leucine (P405R or P425L): the former was a somatic mutation, and the latter was a germ-line mutation. Intriguingly, both missense mutations resided within the COOH-terminal region of p73. To examine whether these naturally occurring missense mutations affect the transactivation ability found in the COOH-terminal region of p73{alpha}, we constructed the GAL4 DNA-binding domain-p73{alpha} mutant (P405R or P425L) fusions based on p73{alpha}(380–513). The expression vectors encoding p73{alpha}(P405R) and p73{alpha}(P425L) were introduced into COS cells together with the reporter gene plasmid pG5CAT, and the CAT activities were measured. As shown in Fig. 5Citation , a remarkable reduction of the CAT activity was observed in both of these mutant forms of p73{alpha}, when compared with that of p73{alpha}(380–513). The similar results were also obtained in HeLa cells (data not shown). These observations suggest that the transactivation activity found in the COOH-terminal region of p73{alpha} is significantly impaired by the missense mutations detected in neuroblastoma.



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  		Fig. 5. Significant reduction of transactivation ability of p73{alpha} COOH-terminal region by missense mutations found in neuroblastomas. A, experiments similar to those described in the legend to Fig. 4Citation were performed using pM-C78 and pM-C119, both of which express mutant forms of p73 COOH-terminal region. After 48 h of transfection, cells were lysed, and CAT activity of each reaction was determined by TLC. B, CAT activity of each transfection is shown as a relative value by setting the CAT conversion activity of the wild-type p73{alpha}(380–513) as 100%. Columns, means (n = 3); bars, SD.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Here, we have shown that, in addition to the NH2-terminal region, the COOH-terminal region of p73 with a glutamine- and proline-rich domain has a transactivation function. The activity is severely impaired in naturally occurring mutants found in neuroblastoma, suggesting that the region plays an important role in regulating growth and survival of the tumor.

Recently, Jost et al. have shown that both p73 isoforms ({alpha} and ß) have an ability to activate the transcription of p53-responsive genes (22) . The striking amino acid sequence similarity between p73 and p53 suggests that the transactivation function of p73 resides within its NH2-terminal region. Indeed, the results that we obtained here in both yeast and mammalian reporter systems have supported it. We have previously found two missense mutations in neuroblastomas, both of which are substitutions of proline residue (P405 and P425) and located in the COOH-terminal region of p73 (residues 380–513). The region is shared between both p73{alpha} and p73ß and is glutamine- and proline-rich, suggesting that the region may confer transcriptional activation (28) . On the basis of the results obtained in the yeast reporter experiments, p73{alpha} (499–636) which lacks those characteristic sequences failed to activate HIS3 and lacZ reporter genes, indicating that the glutamine- and/or the proline-rich sequence might be responsible for the transactivation function found in the COOH-terminal region of p73{alpha}. The region of p73 might further be divided into two segments: a glutamine- and proline-rich region (residues 382–413) and a proline-rich region (residues 425–491; Fig. 1Citation ). The former contains 7 glutamine and 7 proline residues in 32 amino acid residues (44%), whereas the latter contains 3 glutamine and 13 proline residues in 67 amino acid residues (24%). Recently, Osada et al. (19) have discovered a new p53-related gene, termed p51, and identified two major splicing variants (p51A and p51B). As in the case of p73, these p51 isoforms possess additional sequences at their COOH termini, compared with p53. In addition, p51B also contains a glutamine- and a proline-rich sequence within its COOH-terminal extra region, and p51A possesses a glutamine-rich sequence within its COOH-terminal extra region. Therefore, the COOH-terminal region of p51 might also have an activation function that is similar to that of p73.

It appears that, unlike p53, the frequency of mutations in human cancers is rare in both p73 (23 , 30, 31, 32, 33, 34) and p51 (29 , 35) . In addition, the physiological function or role of p73 and p51 might be different from that of p53, although the functions reported, such as induction of growth arrest and apoptosis, are similar among the p53 family members. The significantly high transactivation activity at the COOH-terminal region of p73 and possible presence of a similar function of p51 might distinguish their function from that of p53.

The p73 gene maps to human chromosome 1p36.33, which resides within the commonly deleted region in neuroblastoma and other cancers (36 , 37) , raising a possibility that p73 is one of the tumor suppressor genes (21) . Recently, we have found two point mutations of 140 neuroblastoma cases that result in amino acid substitutions (P450R and P425L) in the COOH-terminal region of p73 (23) . Transient reporter experiments have demonstrated that each missense mutation causes a significant reduction of the transactivation activity. In each mutation, proline residues have been replaced by an arginine or leucine residue, suggesting that proline residues in this segment might be required for the transactivation function. This may also suggest that loss of function mutations in this region might be involved in the development and/or progression of neuroblastoma.

The complex formation between p53 and Mdm2 proteins results in the significant reduction of the transactivation ability of p53 (38) . Because the consensus binding sequence for Mdm2 appears to be present in the NH2-terminal domain of p73 (39) , its activation function might be inhibited by the direct interaction with Mdm2. Under the conditions in which p73 associates with Mdm2, it is possible that p73 could retain the COOH-terminal transactivation activity. Studies are underway in our laboratory to investigate the effect of Mdm2 on the transactivation function of p73.


   ACKNOWLEDGMENTS
 
We thank Dr. S. Sakiyama for encouragement and reading the manuscript and A. Morohasi and N. Sugimitu for their technical assistance.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by a Grant-in-Aid from the Ministry of Health and Welfare for a New 10-Year Strategy for Cancer Control; a Grant-in-Aid from the Ministry of Health and Welfare for the Study Group for Treatment of Advanced Neuroblastoma; Uehara Memorial Foundation; and a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Science, Sports and Culture, Japan. N. T. is an awardee of Research Resident Fellowship from the Foundation for Promotion of Cancer Research, Japan. Back

2 To whom requests for reprints should be addressed, at Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2, Nitona, Chuoh-ku, Chiba 260-8717, Japan. Phone: 81-43-264-5431 Fax: 81-43-265-4459; E-mail: akiranak{at}chibacc.pref.chiba.jp Back

3 The abbreviation used is: CAT, chloramphenicol acetyltransferase. Back

Received 1/25/99. Accepted 4/26/99.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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