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Journal of Virology, October 1998, p. 8392-8395, Vol. 72, No. 10
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Suppression of c-Myc-Induced Apoptosis by the
Epstein-Barr Virus Gene Product BHRF1
Abdallah
Fanidi,*
David C.
Hancock, and
Trevor
D.
Littlewood
Biochemistry of the Cell Nucleus, Imperial
Cancer Research Fund Laboratories, London WC2A 3PX, United Kingdom
Received 30 March 1998/Accepted 13 July 1998
 |
ABSTRACT |
Constitutive expression of the c-myc proto-oncogene in
growth factor-deprived fibroblasts promotes proliferation and induces apoptosis. In these cells, apoptosis can be inhibited by survival factors such as insulin-like growth factor I or the bcl-2
proto-oncogene product. Deregulated c-Myc expression is a common
feature in Epstein-Barr virus-positive Burkitt's lymphoma in which the
c-myc gene is reciprocally translocated and placed under
the control of one of the immunoglobulin loci. BHRF1 is an Epstein-Barr
virus protein expressed early in the lytic cycle. BHRF1 is a member of
the Bcl-2 family and has been shown to suppress apoptosis and to
increase cell survival in different settings. In the present study, we
report that BHRF1 inhibits c-Myc-induced apoptosis which occurs in the
absence of survival factors. It does not, however, affect the capacity
of c-Myc to promote cell growth. These findings demonstrate that BHRF1
has not only structural but also functional similarities to Bcl-2.
| |
TEXT |
The Epstein-Barr virus (EBV) is a
B-lymphotropic human herpesvirus associated with human
lymphoproliferative diseases such as Burkitt's lymphoma (BL) and
Hodgkin's disease. A characteristic feature of EBV is its ability to
infect resting B lymphocytes in vitro, converting them into permanently
growing, immortalized lymphoblastoid cell lines (LCLs) (reviewed in
reference 29). BHRF1 is an EBV gene expressed early
in the EBV lytic cycle. The BHRF1 protein shares 38% primary amino
acid sequence homology with the bcl-2 proto-oncogene product
over its carboxy-terminal region (11, 35, 36). Members of
the Bcl-2-related family share three highly conserved domains:
BH1, BH2 (38), and BH3 (6, 9). Like Bcl-2, BHRF1 possesses a C-terminal hydrophobic region which localizes it to intracellular membranes (19),
primarily to the mitochondrial periphery in transfected cells
(21). Ectopic expression of BHRF1 extends the survival of a
murine interleukin-3 (IL-3)-dependent hemopoietic cell line (32D) upon
removal of IL-3 (31). BHRF1 is also able to protect
serum-deprived or ionomycin-treated BL cell lines (19) from
cell death and to inhibit cisplatin-, etoposide-, and mitomycin-induced
apoptosis in CHO cells (32). In these ways, BHRF1 is
functionally similar to Bcl-2. It is worth noting that both the latency
membrane protein 1 (LMP-1) and EBNA-2 of EBV have been shown to
upregulate Bcl-2 expression and inhibit apoptosis in B cells (16,
20). This suggests that EBV may have evolved mechanisms to
overcome the killing of host cells by expressing a set of antiapoptotic
proteins, thereby allowing viral propagation. The c-myc gene
is the cellular homolog of the viral oncogene v-myc found in
a number of avian and feline retroviruses that induce leukemia,
carcinomas, and sarcomas. Its expression has been associated with cell
proliferation and neoplasia (12, 30). Deregulated c-Myc
expression is frequently associated with BL, a B-cell neoplasia
resulting from the translocation of the c-myc gene from
chromosome 8 to chromosome 2, 14, or 22 (24). The most
frequent translocation, t(8; 14), juxtaposes the c-myc gene
locus on chromosome 8 to the immunoglobulin heavy chain gene locus on
chromosome 14. This translocation places c-myc under the
immediate control of the immunoglobulin promoter.
Deregulated expression of c-Myc accelerates apoptosis in serum-starved
and drug-arrested fibroblasts (14) and in IL-3-dependent myeloid cells upon removal of IL-3 (3). c-Myc-induced
apoptosis can be inhibited by Bcl-2 protein (5, 15, 34). The
proto-oncogene bcl-2 is activated in the majority of
non-Hodgkin's lymphomas as a consequence of t(14; 18)
translocation which juxtaposes the bcl-2 gene adjacent to
the immunoglobulin G locus during immunoglobulin gene rearrangement in
pre-B cells (4, 10, 33). The oncogenic activity of Bcl-2
does not result from an increase in c-Myc-induced proliferation but
rather from an inhibition of the apoptotic function of c-Myc
(15). This functional interaction between c-Myc and Bcl-2
exemplifies a novel form of oncogene cooperation. In order to test
whether BHRF1 interferes with c-Myc cellular activities in a manner
similar to Bcl-2, we investigated its effect on the proliferative and
apoptotic functions of c-Myc.
BHRF1 inhibits c-Myc-induced apoptosis.
Constitutive
expression of c-myc or ectopic activation of the
c-Myc-estrogen receptor fusion protein (13) induces
apoptosis in serum-deprived Rat-1 fibroblasts (14, 15, 17).
In the absence of serum, Rat-1/c-Myc-ER cells downregulate endogenous c-Myc, arrest in G0/G1, and remain viable for
many days. Addition of exogenous 
-estradiol activates c-Myc-ER and
induces the rapid onset of apoptosis in Rat-1 fibroblasts
(14). To test the effect of BHRF1 on the apoptotic and
growth-promoting activities of c-Myc, we infected Rat-1/c-Myc-ER cells
with the retrovirus vector pBabePuro (28) carrying
bhrf1 cDNA. Clones of Rat-1/c-Myc-ER cells stably expressing
bhrf1 mRNA were isolated after selection with 5 µg of
puromycin/ml. Northern blot analysis using a 32P-labeled
bhrf1 cDNA as probe (8) shows the expression of
bhrf1 mRNA in two representative Rat-1/c-Myc-ER/BHRF1
clones, no. 2 and 4 (Fig. 1). Using these
two clones, we first analyzed the effect of BHRF1 on c-Myc-induced
apoptosis. Rat-1/c-Myc-ER/BHRF1 clones and mock-infected Rat-1/c-Myc-ER
cells were rendered quiescent by culturing them for 2 days in
serum-free medium. c-Myc was then activated by the addition of 2 µM
-estradiol, and apoptosis was analyzed by time-lapse videomicroscopy
as previously described (14, 15, 17). Under these
conditions, BHRF1 is a potent inhibitor of c-Myc-induced apoptosis
(Fig. 2). Eight clones constitutively expressing BHRF1 were tested, and all showed a substantial inhibition of c-Myc-induced cell death (not shown). Thus, BHRF1 protein is functionally similar to Bcl-2 (15).
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FIG. 1.
Expression of bhrf1 mRNA in Rat-1/c-Myc-ER
fibroblasts. The expression of BHRF1 in two representative
Rat-1/c-Myc-ER/BHRF1 clones, no. 2 and 4, infected with the retroviral
vector pBabePuro carrying bhrf1 cDNA, was determined by
Northern blotting using a bhrf1 cDNA as probe. Total RNA
extracted from Rat-1/c-Myc-ER cells infected with the empty pBabePuro
vector is shown as a control.
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FIG. 2.
BHRF1 inhibits c-Myc-induced apoptosis. Logarithmically
growing Rat-1/c-Myc-ER control cells and Rat-1/c-Myc-ER/BHRF1 clones 2 and 4 were serum deprived for 48 h. c-Myc was then activated by
the addition of 2 µM -estradiol to the medium. A randomly chosen
field of 100 cells was monitored by time-lapse videomicroscopy at a
rate of one frame every 3 min. Results are expressed as the cumulative
number of apoptotic events plotted against time.
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|
BHRF1 does not affect the growth-promoting activity of c-Myc.
We have previously shown that Bcl-2 inhibits the apoptotic function of
c-Myc without affecting its mitogenic activity (15). We
therefore sought to test whether BHRF1 affects c-Myc-induced proliferation in Rat-1 fibroblasts. Rat-1/c-Myc-ER/BHRF1 lines and
control Rat-1/c-Myc-ER cells were rendered quiescent by serum starvation; then c-Myc was activated by the addition of 2 µM
-estradiol. Individual cell first divisions were scored by
time-lapse videomicroscopy as previously described (14), and
the results are presented as cumulative cell divisions versus time.
Figure 3 shows the mitotic rate of
Rat-1/c-Myc-ER cells in either the presence or absence of BHRF1.
Mitotic rates of control Rat-1/c-Myc-ER cells and those expressing
BHRF1 are similar, suggesting that BHRF1 does not significantly affect
the growth-promoting activity of c-Myc.
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FIG. 3.
BHRF1 does not affect the mitogenic activity of c-Myc.
Subconfluent Rat-1/c-Myc-ER cells and Rat-1/c-Myc-ER/BHRF1 clones 2 and
4 were serum starved for 2 days. c-Myc was then activated by the
addition of 2 µM -estradiol, and a randomly chosen field of 100 cells was monitored by time-lapse videomicroscopy at a rate of one
frame every 3 min. Results are expressed as cumulative first divisions
plotted against time.
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Inhibition of c-Myc-induced death by BHRF1 protein in
thymidine-arrested Rat-1 fibroblasts.
The c-Myc protein is a
potent inducer of apoptosis in Rat-1 fibroblasts which have been
blocked in S phase with an excess of thymidine (14). This
type of cell death can be inhibited by Bcl-2 (15). We
therefore tested whether BHRF1 can inhibit c-Myc-induced apoptosis in
thymidine-blocked fibroblasts. Rat-1/c-Myc-ER cells constitutively
expressing BHRF1 as well as control cells were incubated with 2 mM
thymidine for 24 h. Under these conditions, more than 96% of the
cells arrested in S phase (results not shown), demonstrating that, as
for Bcl-2 (15), BHRF1 does not relieve the cell cycle block
imposed by thymidine. Activation of c-Myc in thymidine-arrested Rat-1
fibroblasts by the addition of 2 µM -estradiol led to rapid cell
death in control cells (Fig. 4). However,
constitutive expression of BHRF1 in Rat-1/c-Myc-ER/BHRF1 cells
substantially delayed and reduced the apoptotic function of c-Myc.
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FIG. 4.
BHRF1 prevents c-Myc-induced apoptosis in
thymidine-treated cells. Subconfluent control Rat-1/c-Myc-ER cells and
Rat-1/c-Myc-ER/BHRF1 clones 2 and 4 were blocked in S phase by
culturing in 2 mM thymidine for 24 h. c-Myc was then activated by
the addition of 2 µM -estradiol to the medium, and a randomly
chosen field of 100 cells was monitored by time lapse videomicroscopy
at a rate of one frame every 3 min. Results are expressed as the
cumulative number of apoptotic events plotted against time.
|
|
In this study, we analyzed the effects of the EBV BHRF1 protein on the
proliferative and the apoptotic functions of c-Myc.
EBV can infect
resting B cells in vitro, leading to the generation
of LCLs. In vivo,
EBV is known to cause infectious mononucleosis.
BHRF1 protein exhibits
a peak of expression early in the EBV lytic
cycle and is also
transiently expressed in latently infected lymphoid
cells
(
27). To date, in vitro studies of the role of BHRF1 in
LCL
development and virus replication have been inconclusive (
26,
27). As previously suggested (
19), BHRF1 may play a
role in
the survival of EBV-infected cells and the development of
EBV-related
tumors in vivo. In addition, deregulated c-Myc expression
is a
common event in BL, resulting from translocations involving
c-
myc and one of the three immunoglobulin loci
(
24). The result is
an excessive expression of c-Myc protein
in B cells, preventing
them from leaving the cycling state. Moreover,
transgenic mice
containing a c-
myc gene linked to the Eµ
immunoglobulin enhancer
develop B-cell tumors (
1,
18). c-Myc
has also been shown
to be a potent inducer of apoptosis in fibroblasts
deprived of
serum or treated with various drugs (
14). Our
results demonstrate
that BHRF1 is a powerful inhibitor of c-Myc-induced
apoptosis
in serum-starved or drug-treated fibroblasts but has no
effect
on the mitogenic activity of c-Myc. It is not clear whether the
cooperative interaction between c-Myc and BHRF1 could result in
oncogenic transformation of EBV-infected cells.
It remains to be established precisely how c-Myc and BHRF1 regulate the
apoptotic machinery. Recent evidence suggests that
c-Myc-induced
apoptosis requires the interaction of Fas and Fas
ligand on the cell
surface (
23). Two mechanisms have been proposed
to explain
the inhibition of cell death by Bcl-2 and its antiapoptotic
homologs.
The first model hypothesizes that antiapoptotic proteins
such as Bcl-2
and Bcl-X
L are able to prevent the release of cytochrome
c from the mitochondria into the cytosol (
25,
37). A second
model suggests that Bcl-2 and Bcl-X
L
regulate the activation of
caspases (
2,
7). In this context,
a recent study has demonstrated
that Bcl-X
L binds to
Apaf-1, a mammalian protein that shares homology
with
Caenorhabditis elegans CED-4, and inhibits the activation
of
caspase 9 (
22). It is tempting to speculate that BHRF1 may
act similarly by affecting caspase activation and/or cytochrome
c release.
| |
FOOTNOTES |
*
Corresponding author. Present address: Onyx
Pharmaceuticals, 3031 Research Dr., Richmond, CA 94806. Phone: (510)
222 9700. Fax: (510) 222 9758. E-mail:
afanidi{at}onyx-pharm.com.
| |
REFERENCES |
| 1.
|
Adams, J. M.,
A. W. Harris,
C. A. Pinkert,
L. M. Corcoran,
W. S. Alexander,
S. Cory,
R. D. Palmiter, and R. L. Brinster.
1985.
The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice.
Nature
318:533-538[Medline].
|
| 2.
|
Armstrong, R. C.,
T. Aja,
J. Xiang,
S. Gaur,
J. F. Krebs,
K. Hoang,
X. Bai,
S. J. Korsmeyer,
D. S. Karanewsky,
L. C. Fritz, and K. J. Tomaselli.
1996.
Fas-induced activation of the cell death-related protease CPP32 is inhibited by Bcl-2 and by ICE family protease inhibitors.
J. Biol. Chem.
271:16850-16855[Abstract/Free Full Text].
|
| 3.
|
Askew, D. S.,
R. A. Ashmun,
B. C. Simmons, and J. L. Cleveland.
1991.
Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis.
Oncogene
6:1915-1922[Medline].
|
| 4.
|
Bakhshi, A.,
J. P. Jensen,
P. Goldman,
J. J. Wright,
O. W. McBride,
A. L. Epstein, and S. J. Korsmeyer.
1985.
Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18.
Cell
41:889-906.
|
| 5.
|
Bissonnette, R. P.,
F. Echeveri,
A. Mahboubi, and D. Green.
1992.
Apoptotic cell death induced by c-myc is inhibited by bcl-2.
Nature
359:552-554[Medline].
|
| 6.
|
Boyd, J. M.,
J. G. Gallo,
A. B. Elangovan,
S. M. Malstrom,
B. J. Avery,
R. G. Ebb,
T. Subramanian,
T. Chittenden,
R. J. Lut, and G. Chinnadurai.
1995.
Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins.
Oncogene
11:1921-1928[Medline].
|
| 7.
|
Chinnaiyan, A. M.,
K. Orth,
K. O'Rourke,
H. Duan,
G. G. Poirier, and V. M. Dixit.
1996.
Molecular ordering of the cell death pathway: Bcl-2 and Bcl-xL function upstream of the CED-3-like apoptotic proteases.
J. Biol. Chem.
271:4573-4576[Abstract/Free Full Text].
|
| 8.
|
Chirgwin, J. M.,
A. E. Przybyla,
R. J. MacDonald, and W. J. Rutter.
1979.
Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease.
Biochemistry
18:5294-5299[Medline].
|
| 9.
|
Chittenden, T.,
E. A. Harrington,
R. O'connor,
C. Flemington,
R. J. Lutz,
G. I. Evan, and B. C. Guild.
1995.
Induction of apoptosis by the Bcl-2 homologue Bak.
Nature
374:733-734[Medline].
|
| 10.
|
Cleary, M. L., and J. Sklar.
1985.
Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18.
Proc. Natl. Acad. Sci. USA
82:7439-7443[Abstract/Free Full Text].
|
| 11.
|
Cleary, M. L.,
S. D. Smith, and J. Sklar.
1986.
Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from t(14; 18) translocation.
Cell
47:19-28[Medline].
|
| 12.
|
DePinho, R. A.,
N. Schreiber-Agus, and F. W. Alt.
1991.
Myc family oncogenes in the development of normal and neoplastic cells.
Adv. Cancer Res.
57:1-46[Medline].
|
| 13.
|
Eilers, M.,
D. Picard,
K. R. Yamamoto, and M. J. Bishop.
1989.
Chimaeras between the MYC oncoprotein and steroid receptors cause hormone-dependent transformation of cells.
Nature
340:66-68[Medline].
|
| 14.
|
Evan, G. I.,
A. H. Wyllie,
C. S. Gilbert,
T. D. Littlewood,
H. Land,
M. Brooks,
C. M. Waters,
L. Z. Penn, and D. C. Hancock.
1992.
Induction of apoptosis in fibroblasts by c-Myc protein.
Cell
69:119-128[Medline].
|
| 15.
|
Fanidi, A.,
E. A. Harrington, and G. I. Evan.
1992.
Cooperative interaction between c-myc and bcl-2 proto-oncogenes.
Nature
359:554-556[Medline].
|
| 16.
|
Finke, J.,
R. Fritzen,
P. Ternes,
P. Trivedi,
K. J. Bross,
W. Lange,
R. Mertelsmann, and G. Dolken.
1992.
Expression of bcl-2 in Burkitt's lymphoma cell lines: induction by latent Epstein-Barr virus genes.
Blood
80:459-469[Abstract/Free Full Text].
|
| 17.
|
Harrington, E. A.,
M. R. Bennett,
A. Fanidi, and G. I. Evan.
1994.
c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines.
EMBO J.
13:3286-3295[Medline].
|
| 18.
|
Harris, A. W.,
C. A. Pinkert,
M. Crawford,
W. Y. Langdon,
R. L. Brinster, and J. M. Adams.
1988.
The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells.
J. Exp. Med.
167:353-371[Abstract/Free Full Text].
|
| 19.
|
Henderson, S.,
D. Huen,
M. Rowe,
C. Dawson,
G. Johnson, and A. Rickinson.
1993.
Epstein-Barr virus-coded BHRF1 protein, a viral homologue of bcl-2, protects B cells from programmed cell death.
Proc. Natl. Acad. Sci. USA
90:8479-8483[Abstract/Free Full Text].
|
| 20.
|
Henderson, S.,
M. Rowe,
C. Gregory,
D. Croom-Carter,
F. Wang,
R. Longnecker,
E. Kieff, and A. B. Rickinson.
1991.
Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death.
Cell
65:1107-1115[Medline].
|
| 21.
|
Hickish, T.,
D. Robertson,
P. Clarke,
M. Hill,
F. di Stefano,
C. Clarke, and D. Cunningham.
1994.
Ultrastructural localization of BHRF1: an Epstein-Barr virus gene product which has homology with Bcl-2.
Cancer Res.
54:2808-2811[Abstract/Free Full Text].
|
| 22.
|
Hu, Y.,
M. A. Benedict,
D. Wu,
N. Inohara, and G. Nunez.
1998.
Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation.
Proc. Natl. Acad. Sci. USA
95:4386-4391[Abstract/Free Full Text].
|
| 23.
|
Hueber, A.-O.,
M. Zornig,
D. Lyon,
S. Nagata, and G. I. Evan.
1997.
Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis.
Science
278:1305-1309[Abstract/Free Full Text].
|
| 24.
|
Klein, G.
1989.
Multiple phenotypic consequences of the Ig/Myc translocation in B-cell-derived tumors.
Gene Chromosomes Cancer
1:3-8.
|
| 25.
|
Kluck, R. M.,
E. Bossy-Wetzel,
D. R. Green, and D. D. Newmeyer.
1997.
The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis.
Science
275:1132-1136[Abstract/Free Full Text].
|
| 26.
|
Lee, M. A., and J. L. Yates.
1992.
BHRF1 of Epstein-Barr virus, which is homologous to human proto-oncogene bcl2, is not essential for transformation of B cells or for virus replication in vitro.
J. Virol.
66:1899-1906[Abstract/Free Full Text].
|
| 27.
|
Marchini, A.,
B. Tomkinson,
J. I. Cohen, and E. Kieff.
1991.
BHRF1, the Epstein-Barr virus gene with homology to Bcl2, is dispensable for B-lymphocyte transformation and virus replication.
J. Virol.
65:5991-6000[Abstract/Free Full Text].
|
| 28.
|
Morgenstern, J. P., and H. Land.
1990.
Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line.
Nucleic Acids Res.
18:3587-3596[Abstract/Free Full Text].
|
| 29.
|
Rickinson, A. B., and E. Kieff.
1996.
Epstein-Barr virus, p. 2397-2446.
In
B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields virology. Lippincott-Raven, Philadelphia, Pa.
|
| 30.
|
Spencer, C. A., and M. Groudine.
1990.
Control of c-myc regulation in normal and neoplastic cells.
Adv. Cancer Res.
56:1-48.
|
| 31.
|
Takayama, S.,
D. L. Cazals-Hatem,
S. Kitada,
S. Tanaka,
T. Miyashita,
L. R. Hovey,
D. Huen,
A. Rickinson,
P. Veerapandian,
S. Krajewski,
S. Saito, and J. Reed.
1994.
Evolutionary conservation of function among mammalian, avian, and viral homologs of the Bcl-2 oncoprotein.
DNA Cell Biol.
13:679-692[Medline].
|
| 32.
|
Tarodi, B.,
T. Subramanian, and G. Chinnadurai.
1994.
Epstein-Barr virus BHRF1 heterologous viral infection.
Virology
150:381-389.
|
| 33.
|
Tsujimoto, Y.,
J. Gorham,
J. Cossman,
E. Jaffe, and C. M. Croce.
1985.
Involvement of the bcl-2 gene in human follicular lymphoma.
Science
228:1440-1443[Abstract/Free Full Text].
|
| 34.
|
Wagner, A. J.,
M. B. Small, and N. Hay.
1993.
Myc-mediated apoptosis is blocked by ectopic expression of Bcl-2.
Mol. Cell. Biol.
13:2432-2440[Abstract/Free Full Text].
|
| 35.
|
Williams, G. T.
1991.
Programmed cell death: apoptosis and oncogenesis.
Cell
65:1097-1098[Medline].
|
| 36.
|
Williams, G. T., and C. A. Smith.
1993.
Molecular regulation of apoptosis: genetic controls on cell death.
Cell
74:777-779[Medline].
|
| 37.
|
Yang, J.,
X. Liu,
K. Bhalla,
C. N. Kim,
A. M. Ibrado,
J. Cai,
T.-I. Peng,
D. P. Jones, and X. Wang.
1997.
Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.
Science
275:1129-1132[Abstract/Free Full Text].
|
| 38.
|
Yin, X.-M.,
Z. N. Oltvai, and S. J. Korsmeyer.
1994.
BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax.
Nature
369:321-323[Medline].
|
Journal of Virology, October 1998, p. 8392-8395, Vol. 72, No. 10
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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-
Meseda, C. A., Arrand, J. R., Mackett, M.
(2000). Herpesvirus papio encodes a functional homologue of the Epstein-Barr virus apoptosis suppressor, BHRF1. J. Gen. Virol.
81: 1801-1805
[Abstract]
[Full Text]
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Bellows, D. S., Chau, B. N., Lee, P., Lazebnik, Y., Burns, W. H., Hardwick, J. M.
(2000). Antiapoptotic Herpesvirus Bcl-2 Homologs Escape Caspase-Mediated Conversion to Proapoptotic Proteins. J. Virol.
74: 5024-5031
[Abstract]
[Full Text]
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