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[Cancer Research 62, 346-350, January 15, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

The NH2-Terminal and Conserved Region 2 Domains of Adenovirus E1A Mediate Two Distinct Mechanisms of Tumor Suppression1

Jiong Deng, Freke Kloosterbooer, Weiya Xia and Mien-Chie Hung2

Department of Molecular and Cellular Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Adenovirus E1A has been shown to suppress tumor growth and induce apoptosis in response to stress. To determine the mechanisms and regions of E1A that mediate these functions, we characterized stable transfectants of various E1A mutants in murine melanoma cells both in vitro and in vivo. Three E1A-mutant constructs were used in this study, those having a single deletion at either the NH2-terminal (dl1101) or conserved region 2 (CR2) domain (dl1108), or double deletions at both domains (dl0108). The in vitro study showed that the CR2 domain is required for E1A-mediated apoptosis, whereas the NH2-terminal domain is dispensable. The in vivo study showed that dl1101 and dl1108 were still able to suppress tumor growth, whereas dl0108 lost tumor-suppressive activity. By in situ immunohistostaining, we found that factor VIII, a marker for angiogenesis, was greatly suppressed in dl1108 transfectants that are resistant to apoptosis. Thus, inhibition of angiogenesis is involved in the NH2-terminal domain of E1A. In conclusion, we suggest that the NH2-terminal and CR2 domain of E1A mediate two distinct mechanisms of tumor suppression.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The E1A gene has been shown to have tumor-suppressive activity (1 , 2) . This function may include transcriptional repression of the HER-2/neu proto-oncogene (3) , conversion of tumor cells to an epithelial phenotype (4) , suppression of metastatic potential (5) , induction of apoptosis (6) , and increasing sensitivity to tumor necrosis factor (7 , 8) . Thus, multiple mechanisms have been implicated in E1A-mediated tumor suppression. The biological functions mediated by E1A are intrinsically associated with their ability to interact with several cellular proteins that are important for the regulation of gene expression and cell growth. These include the CBP3 (9) , p300 (10) , pRB (10) , p130, p107, and CtBP. Genetic analyses have identified a strong correlation between E1A activity and its ability to bind to these factors, particularly p300 and pRB (10) . It is assumed that by binding to these proteins, E1A alters or inhibits their normal functions in the cell, reprogramming cell growth, and differentiation. We hypothesize that the functional domains of E1A that interact with these proteins are also required for E1A-mediated tumor suppression.

We showed previously that E1A-induced apoptosis is associated with E1A-mediated tumor suppression (11) . To additionally investigate the mechanisms of E1A-mediated tumor suppression, we characterized both in vitro and in vivo the biological properties of stable transfectants of a series of E1A mutants that have a deletion at the NH2-terminal domain (p300-binding), CR2 domain (pRb-binding), or both. The results of this study indicate that the NH2-terminal and CR2 domains of E1A mediate two distinct mechanisms of tumor suppression.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Cell Lines, Plasmids, and DNA Transfection.
Murine melanoma cell line K1735-M2 was described previously (11 , 12) , as were pE1A-neo (11) , E1A mutants dl1101 (having a single deletion at amino acid residues 5–23 at NH2 terminus), dl1108 (having a single deletion at amino acid residues 125–126), and dl0108 (having double deletions at both regions; Fig. 1ACitation ; Refs. 8 , 13 , 14 ). The E1A-mutant plasmids were cotransfected into cells with pSV2-neo. DNA transfection was performed by lipofection, and cell cultures were performed as described (11) . All of the transfectants were selected in medium containing G418 (500 µg/ml, respectively). Expression of E1A gene products was examined via immunoblot analysis as described previously (11) . The primary monoclonal antibody used was M53 against the E1A proteins (PharMingen, San Diego, CA).



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  		Fig. 1. The CR2 domain of E1A is required for E1A-mediated apoptosis. A, map of E1A and E1A mutants used in this study (8 , 14) . B, immunoblot against E1A in stable transfectants of E1A and E1A mutants. C, DNA fragmentation of stable transfectants of E1A and E1A mutants after serum depletion (2 days in 0.1% serum).

 
Apoptosis Analysis.
Serum deprivation was performed using medium containing 0.1% FCS. Ionizing radiation was performed using Co60 source at an indicated dose. UV irradiation was performed using UV-C at an indicted dose. Low molecular weight DNA was extracted from cells and analyzed as described (11) . Quantitative analysis of apoptotic cells was performed using FACS as described (11) . Briefly, trypsinized cells were washed with PBS and then fixed with 70% ethanol at 4°C. Before analysis, cells were washed with PBS and then added to a fluorochrome solution (50 µg/ml propidium iodide in 0.1% sodium citrate plus 0.1% Triton X-100).

Tumorigenicity Analysis.
Specific pathogen-free female BALB/c athymic nude (nu/nu) and syngenic C3H/HeN (H-2k) mice (6–8 weeks old) were obtained from Harlan Sprague Dawley, Inc. (Indianapolis, IN). The animals were cared for and used in accordance with institutional guidelines. Cells in log-phase growth were trypsinized, washed twice with PBS, and centrifuged at 1000 x g. Viable cells were counted; 1 x 106 cells in 0.2 ml of serum-free medium was then injected s.c. into one flank of the mice. Tumor volume was estimated as the product of three-dimensional caliper measurements.

Immunohistochemistry.
About 10 days after inoculation, histological sections of tumor tissues obtained from nude mice were routinely fixed with formalin buffer and embedded in paraffin. The immunoperoxidase staining method used was modified from the avidin-biotin complex technique (15) . Specifically, the sections were incubated with a rabbit antibody against factor VIII (1:200; DAKO Corp., Carpinteria, CA; Ref. 15 ), then they were incubated with biotinylated goat antirabbit IgG (1:200; Vector Laboratories, Inc., Burlingame, CA). Next, the sections were incubated with an avidin-biotin complex/horseradish peroxidase conjugate and developed using aminoethylcabazole chromogen (Sigma Chemical Co., St. Louis, MO) as a substrate. Positive signals were visualized by light microscopy at high power (x400), and the number of microvessels in 10 x 200 fields was counted for each tumor section.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
The CR2 (pRb-binding) Domain of E1A Is Required for E1A-mediated Apoptosis.
We showed previously that E1A-mediated apoptosis is associated with E1A-mediated tumor suppression (11) . To determine which regions of E1A are responsible for apoptosis and tumor suppression, we characterized the stable transfectants of a series of E1A mutants having a deletion at the NH2-terminal domain (dl1101), CR2 domain (dl1108), or both (dl0108). The genetic map of E1A and its mutants are shown in Fig. 1ACitation . We first established E1A-mutant stable transfectants via transfection of parental K1735-M2 cell lines with corresponding E1A-mutant constructs. Immunoblot analysis indicated that the E1A gene products were expressed by these stable transfectants (Fig. 1B)Citation . At least two subclones of each of the transfectants derived from either E1A or E1A-mutant constructs were used for biological characterization both in vitro and in vivo in most of the subsequent experiments described in this study.

Next, we analyzed the apoptotic susceptibility of these cell lines to stresses, serum depletion, and UV and {gamma}-radiation in vitro. The apoptotic cells were examined using morphology (data not shown), DNA fragmentation (Fig. 1C)Citation , and FACS analysis (Table 1)Citation . E1A (KA4 and KA9) and dl1101 transfectants (K01.2 and K01.9) underwent apoptosis after treatment using these stresses, whereas, dl1108 (K08.2 and K08.5; Fig. 2, B and CCitation ; Table 1Citation ) and dl0108 (K0108.3 and K0108.5; data not shown) were resistant to such treatment. These data suggest that the CR2 (pRb-binding) domain of E1A is required for E1A-mediated apoptosis but that the NH2-terminal (p300-binding) domain is dispensable.


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  		Table 1 Analysis of apoptotic cells using FACS

 


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  		Fig. 2. The NH2-terminal and CR2 domains of E1A are responsible for tumor-suppressive activity. A, tumorigenicity in immunodeficient nude mice. Mice were injected s.c. with 1–1.5 x 106 cells on one flank. B, tumorigenicity in immune-competent syngenic C3H mice. Injection was performed similarly to that in nude mice. C, immunoblot against E1A in tumor cell line and tumor cells isolated from mice. Tumors isolated from the mice were prepared as tumor cell lysates and subjected to immunoblotting against E1A; bars, ±SD.

 
Two Different Mechanisms Are Implicated in E1A-mediated Tumor Suppression.
To determine which regions of E1A are required for tumor suppression, we analyzed the tumorigenicity of different E1A-mutant transfectants in vivo. The tumorigenicity study of each transfectant was first performed in immunodeficient athymic nude mice. The mice, in groups of five, then received an s.c. injection of corresponding tumor cells (1 x 106) and were monitored for tumor growth. The tumorigenicity of E1A (KA4 and KA9), dl1101 (K01.2 and K01.9), and dl1108 transfectants (K08.2 and K08.5) was greatly suppressed in nude mice, whereas that of dl0108 transfectants (K0108.3 and K0108.5) was largely restored (Fig. 2A)Citation . This suggests that E1A mutants having a single deletion at either the NH2-terminal (dl1101) or CR2 domain (dl1108) were still able to mediate tumor suppression, whereas E1A mutants having double deletions at both domains lost tumor-suppressive activity. This conclusion was additionally verified by a similar study performed in immunocompetent syngenic C3H mice, which gave a more clear-cut result. The tumorigenicity of E1A, dl1101, and dl1108 transfectants was completely eliminated in C3H mice (Fig. 2B)Citation rather than greatly suppressed in nude mice (Fig. 2A)Citation .

To rule out the possibility that the restored tumors (K0108.3 and K0108.5) were derived from the cells that lost the E1A gene during cell proliferation or tumor growth, we examined the gene expression in these tumors isolated from mice. We found that the tumors still expressed the mutant E1A gene (Fig. 2C)Citation , which suggests that dl0108 indeed lost tumor-suppressive activity. Thus, we concluded that either the NH2-terminal or CR2 domain of E1A is able to mediate tumor suppression and that both domains are required for E1A-mediated tumor suppression. However, the biological activities of dl1101 and dl1108 transfectants are different, in which dl1101 transfectants are sensitive to stresses, whereas dl1108 transfectants are not. This suggests that different mechanisms of tumor suppression may be involved in the NH2-terminal and CR2 domains of E1A. Because dl1108 and dl1101 transfectants have different sensitivity to stress-induced apoptosis, it implies that the tumor suppression through the NH2-terminal domain and CR2 domain is different.

The NH2-terminal (p300-binding) Domain of E1A Is Associated with Inhibition of Angiogenesis.
The NH2-terminal domain of E1A is known to interact with p300/CBP and inactivate p300/CBP-mediated function (10) . This domain has been linked with suppression of VEGF expression (16) . VEGF is significant in that it promotes angiogenesis, which is important for tumor growth. Because factor VIII, which presents in the endothelial cells of blood vessel, has been used as a marker for angiogenesis (17) , we examined its expression in tumor tissues isolated from nude mice using in situ immunohistostaining. Also, to determine whether inhibition of angiogenesis is involved in E1A-mediated tumor suppression, we examined tissues samples of tumors arising from different transfectants, which were obtained ~10 days after inoculation. Representative pictures show that factor VIII-positive cells were present in the transfectants KSP (Fig. 3A)Citation and K0108.5 (Fig. 3D)Citation but not KA9 (Fig. 3B)Citation or K08.5 (Fig. 3C)Citation . By discrete microvessel counts, we found that neovascularization in the tumors induced in KA9 and K08.5 (0–2%) were dramatically lower than those induced by K, KSP, and K0108.5 (12–20%), and K01.9 (8%; Fig. 4ECitation ). Thus, the angiogenic process was dramatically suppressed in the transfectants of dl1108 and E1A, which correlates with the observed tumor suppression in vivo. Therefore, inhibition of angiogenesis is likely to be involved in the tumor-suppressive activity mediated by the NH2-terminal domain of E1A, which may contribute to tumor suppression in vivo.



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  		Fig. 3. The NH2-terminal domain of E1A is associated with angiogenesis inhibition. Representative view of immunohistochemical staining for factor VIII in tumor tissues derived from E1A, mutant E1A, and vector transfectants, A, KSP. B, KA9. C, K08.5. D, K0108.5. E, average of total counts of microvessels in 10 fields in tumor tissues derived from different cell lines as indicated; bars, ±SD.

 


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  		Fig. 4. Model of two different mechanisms of E1A-mediated tumor suppression.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
In this study, we characterized the stable transfectants of E1A mutants having deletions at different functional domains. On the basis of both in vitro and in vivo analysis, we made the following observations. First, stable transfectants of dl1108 (having a single deletion at the CR2 domain) lost sensitivity to stresses, whereas the transfectants of dl1101 (having a single deletion at the NH2-terminal domain) were sensitive to stresses. This observation suggests that the CR2 domain is required for E1A-mediated apoptosis, whereas the NH2-terminal domain is dispensable. Second, E1A-mutant transfectants having a single deletion at either the NH2-terminal (dl1101) or CR2 domain (dl1108) were nontumorigenic, whereas those having double deletion at both domains (dl0108) were tumorigenic. This observation suggests that the NH2-terminal and CR2 domains are mainly responsible for E1A-mediated tumor suppression. Third, the tumor tissues of the dl1108 transfectants exhibited a suppressed angiogenesis although they lost sensitivity to stress. This observation suggests that inhibition of angiogenesis is involved in the functions mediated by the NH2-terminal domain. Because the NH2-terminal and CR2 domains of E1A are responsible for tumor suppression and associated with different biological activities, two different mechanisms through two different regions of E1A are suggested to be responsible for E1A-induced tumor suppression.

The CR2 domain of E1A has been shown to interact with cellular proteins, pRb, and members of the pRb family. This interaction may result in several molecular consequences, association with and inactivation of pRb, dissociation of the E2F-Rb complex, and release of the transcription factor E2F (18) . Deregulated E2F can disrupt cells cycle regulation and enforce S phase entry, which leads to either cell proliferation or apoptosis (19) . Recently, E2F-1 has also been shown to have tumor suppressor function. It was found that E2F-1-null transgenic mice were prone to developing various types of cancers (20) , and blocking the transcription factor E2F/DP by dominant-negative mutants in a normal breast epithelial cell line efficiently inhibited apoptosis and induced tumor growth in severe combined immunodeficiency mice (21) . The apoptotic activity of E2F-1 has been shown to go through inhibition of nuclear factor {kappa}B and/or induction of p53 (22) , which may be responsible for the tumor-suppressive activity. The murine melanoma cell line K1735 M2 used in this study contains wild-type p53. Thus, it is possible that E2F-1-mediated p53 induction may be involved in the CR2 domain-induced apoptosis. However, it should be noticed that E2F-1 also induces apoptosis in a p53-independent manner (23) . Additional systemic study is required to find out all of the signal pathways that may be involved in the CR2 domain-mediated apoptosis and tumor suppression.

The NH2-terminal domain of E1A is associated with its ability to interact with the cellular protein p300/CBP, which is a member of a family of transcriptional coactivators. p300/CBP is known to bind with specific enhancer-binding proteins as well as the proteins involved in the regulation of transcription of several genes (24, 25, 26) . By interaction with p300/CBP, E1A, through its NH2-terminal domain, can deplete p300 and inactivate p300/CBP-mediated functions. Recently, the NH2-terminal domain of E1A has been linked with the activity of angiogenesis inhibition, as studies have shown that hypoxia-induced VEGF expression requires a functional transcriptional complex that contains both hypoxia-inducible factor and p300/CBP. Specifically, it has been shown that this transcription can be inhibited by E1A and that the inhibitory activity of E1A has been mapped to its NH2-terminal domain (16) . Consistent with these studies, we found that angiogenic activity of dl1108 tumors in vivo was dramatically suppressed. Thus, inhibition of angiogenesis by the depletion of p300 through the NH2-terminal domain of E1A is implicated as a mechanism of E1A-mediated tumor suppression in vivo. Therefore, we propose that the NH2-terminal and CR2 domains are mainly responsible for E1A-mediated tumor suppression; the CR2 domain is associated with apoptosis induction, whereas the NH2-terminal domain is associated with angiogenesis inhibition, which contributes to E1A-mediated tumor suppression (Fig. 4)Citation .

In summary, this study has shown that the CR2 domain of E1A is required for E1A-mediated apoptosis, whereas the NH2-terminal domain is associated with inhibition of angiogenesis. These domains mediate two distinct mechanisms of tumor suppression.


   ACKNOWLEDGMENTS
 
We thank Dr. Stanley T. Bayley for providing the mutant E1A plasmid constructs.


   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 Supported by Grants R01 CA58880, CA77858, and Cancer Center Core Grant 16672 from the National Cancer Institute, M. D. Anderson Faculty Achievement Award, and the Breast Cancer Research Program. Back

2 To whom requests for reprints should be addressed, at Department of Molecular and Cellular Oncology, Box 79, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030. Phone: (713) 792-3668; Fax: (713) 794-0209; E-mail: mhung{at}notes.mdacc.tmc.edu Back

3 The abbreviations used are: CBP, cAMP-responsive element binding protein (CREB) binding protein; CR2, conserved region; VEGF, vascular endothelial growth factor; FACS, fluorescence-activated cells sorter. Back

Received 8/17/01. Accepted 11/30/01.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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