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Division of Reproductive Biology Department of Gynecology and Obstetrics Stanford University School of Medicine Stanford, California 94305-5317
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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A growing body of evidence suggests that the intracellular death program activated during apoptosis is similar in different cell types and conserved during evolution (1, 3, 4). The protooncogene Bcl-2 was isolated at the breakpoint of the t(14, 18) chromosomal translocation associated with follicular B cell lymphoma (5, 6). Overexpression of the Bcl-2 protein suppresses apoptosis induced by a variety of agents both in vitro and in vivo (7). Subsequent studies identified a number of Bcl-2-related proteins possessing several conserved BH (Bcl-2 homology) domains important for homo- or heterodimerization between family members (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). In addition, a C-terminal membrane-anchoring region important for subcellular localization is found in some members. Based on their differential ability to regulate apoptosis, the Bcl-2-related proteins can be separated into anti- and proapoptotic members, and the balance between these counteracting proteins presumably determines the cell fate (1, 8, 9). Based on studies in mice with deletion of different Bcl-2-related proteins (20, 21, 22) and studies on differential interactions among multiple Bcl-2-related proteins (18, 23), it is becoming clear that the balance of cell survival or apoptosis is maintained by different combinations of Bcl-2 family proteins in a tissue-, dimerization-, and circumstance-specific manner. In addition, Bcl-2 family proteins, represented by Bcl-xL, could regulate the activities of downstream apoptotic effectors, capases, by forming a functional complex with Apaf-1 and caspase 9 (24). Furthermore, Bcl-2 proteins containing the BH1, BH2, and BH3 domains have been shown to form ion channels and regulate osmotic changes in mitochondria and other subcellular compartments, leading to the release of cytochrome c, an important cofactor for caspase activation (25, 26, 27, 28, 29). In contrast to the membrane-bound Bcl-2 proteins, several soluble Bcl-2 proteins such as BAD (Bcl-xL/Bcl-2-associated death promoter) and BID (BH3 interacting domain death agonist), containing only the BH3 domain, are likely to function as adaptor proteins linking the membrane-bound family proteins and cytoplasmic signaling molecules (13, 15, 30, 31).
In the ovary, overexpression of Bcl-2 in transgenic mice led to the suppression of follicle cell apoptosis and subsequent formation of teratoma of germ cell origin (32), whereas deletion of the proapoptotic Bax gene resulted in the accumulation of apoptotic follicular cells (21). These data suggest that the Bcl-2 family proteins have important roles in the regulation of follicular atresia. In preliminary studies, we found that an antiapoptotic Bcl-2 family protein Mcl-1, but not Bcl-2 itself, was highly expressed in ovarian follicles, suggesting that Mcl-1 could regulate ovarian follicle atresia. Using Mcl-1 as bait to screen an ovarian fusion cDNA library in the yeast two-hybrid system, we isolated Bok (Bcl-2-related ovarian killer), a new proapoptotic Bcl-2 family member expressed mainly in the ovary, uterus, and testis (18). In the present study, we report the isolation of another proapoptotic protein, Bcl-2-related ovarian death agonist (BOD), using the Mcl-1 bait in the yeast two-hybrid screen. BOD encodes a protein containing a consensus BH3 domain known to be important for the heterodimerization of Bcl-2 proteins and the cell-killing activity of proapoptotic Bcl-2 members. Unlike Bok, BOD shows a wide heterodimerization property by binding to diverse anti- but not proapoptotic Bcl-2 proteins. In addition, BOD is expressed in a variety of tissues and could play regulatory roles on cell death in diverse cell lineages. Future characterization of the role of BOD in apoptosis could provide new understandings on intracellular mechanisms of cell death regulation in the ovary and other tissues.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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). GenBank accession numbers for BOD-L,
BOD-M, and BOD-S are AF065433, AF065432, and AF065431,
respectively.
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, lightly hatched residues). However, the
length of this hydrophobic region is short (15 amino acids), suggesting
the putative transmembrane domain in BOD is atypical. The N-terminal
region of BOD-L is rich in proline and serine residues, and multiple
potential phosphorylation sites were found along the entire length of
BOD-L (Fig. 1A). Nucleotide sequence analysis further suggested that
BOD-M is a splicing variant of BOD-L, whereas BOD-S could derive from
the usage of an alternative transcription starting site because its
translation start site is preceded by nucleotide sequences different
from that of BOD-L and BOD-M (data deposited in the GenBank).
Comparison of DNA sequences with known genes in the GenBank using the
BLAST server indicated that BOD is a novel member of the Bcl-2 family
of proteins showing only the conserved BH3 domains but lacking the BH1,
BH2, and BH4 domains found in channel-forming Bcl-2 proteins. The core
sequence of the BH3 domain found in BOD (LRRIGDE) is the same as that
of rat and mouse Bax, but the flanking sequences are different.
Comparison of the BH3 domain and flanking sequences in BOD, Bcl-xL, and
BAD (Fig. 1B) indicated that, in addition to the core sequence
(LRRIGDE), the flanking regions are also partially conserved.
During the preparation of our manuscript, the mouse Bim gene was
isolated in an expression screen for proteins capable of binding Bcl-2
from a lymphoma cell line (19). Based on sequence similarity, the
present rat BOD gene is likely the ortholog of mouse Bim. However, the
shortest splicing variant of rat BOD (BOD-S) is shorter than any of the
reported Bim variants.
BOD Heterodimerized with Different Antiapoptotic Bcl-2 Proteins
Using the yeast two-hybrid system, interactions between BOD and
different anti- and proapoptotic Bcl-2 proteins were studied. As shown
in Fig. 2, BOD-L, BOD-M, and BOD-S
interacted strongly with diverse antiapoptotic proteins including
Mcl-1, Bcl-2, Bcl-xL, Bcl-w, Bfl-1, and the Epstein-Barr viral-derived
BHRF-1. In contrast, no interaction was observed between different BOD
variants and several proapoptotic Bcl-2 proteins (BAD, Bak, Bok, and
Bax). Because our original screening indicated that the C-terminal 60
amino acids of BOD are sufficient for interaction with Mcl-1 in the
yeast two-hybrid system, a truncated construct containing only the
C-terminal 70 amino acids of BOD was also tested for interaction with
different Bcl-2 family proteins. As expected, this extra short
construct (named BOD-ES) showed strong interactions with all
antiapoptotic proteins tested (Fig. 2), suggesting that the C-terminal
BH3 domain-containing region is the functional motif for BOD to
interact with other Bcl-2 proteins. To demonstrate that the lack of
interactions between BOD and proapoptotic Bcl-2 proteins was not due to
the killing of yeast cells by these death agonists, we also tested the
growth of yeast cells cotransformed with different proapoptotic
proteins and Bcl-xL or Mcl-1. Although all the proapoptotic members
tested showed negligible interaction with BOD, they interacted strongly
with Bcl-xL or Mcl-1 (data not shown).
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, transfection with expression
plasmids encoding different BOD-splicing variants (BOD-L, BOD-M, and
BOD-S) and BOD-ES using the ß-galactosidase cotransfection assay
resulted in a loss of greater than 98% of viable cells as compared
with the control group transfected with an empty vector. In contrast,
cells transfected with the plasmid with different BOD variant cDNAs in
reverse orientation remained viable (Fig. 3A).
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, induction of apoptosis by BOD-L and
BOD-ES was reduced after cotransfection with P35 (P <
0.01), suggesting the involvement of a caspase-mediated proteolysis
cascade. In contrast, transfection with the P35 expression vector alone
did not affect cell survival. To test the ability of antiapoptotic
Bcl-2 proteins to modulate BOD-induced apoptosis, CHO cells were
cotransfected with vectors encoding BOD and Bcl-w (36), a Bcl-2 protein
showing high affinity for different BOD variants in the yeast
two-hybrid assay. As shown in Fig. 3B, the ability of BOD-L or BOD-ES
to induce apoptosis was reduced after cotransfection with the
expression vector encoding Bcl-w (P < 0.01).
To further study the role of the putative BH3 region of BOD in its
cell- killing ability, we mutated the BH3 region in the shortest
splicing variant (BOD-S) that is still capable of inducing apoptosis.
As shown in Fig. 4, mutations of the core
BH3 sequence in BOD-S from LRRIGDE to AAAAADE (BOD-S 5A) completely
abolished its proapoptotic activity in transfected CHO cells.
Furthermore, we generated the same mutations in the truncated BOD-ES
with only 70 amino acids in the C-terminal sequence of BOD (BOD-ES 5A)
and found that this mutant also lost its proapoptotic activity.
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). One main transcript with a size of
approximately 5.5 kb was found in diverse tissues of both species. In
addition to the major transcript, a less prominent transcript of 3.0 kb
was detected in the rat spleen and human leukocyte, whereas a band of
1.3 kb was also detected in the testis of human and rat. These
different mRNA species could result from the use of alternative
polyadenylation sites and/or the alternative splicing of the BOD
gene.
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). These data suggest
that the BOD gene is well conserved in mammals during evolution.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Recent studies suggested that the region spanning BH1 and BH2 domains of Bcl-2 proteins is important for pore formation in the artificial membrane and could function as ion channels in the mitochondria as well as other subcellular membrane organelles (3). Furthermore, the amphipathic BH3 domain in proapoptotic Bcl-2 proteins might regulate apoptosis by binding to a hydrophobic cleft formed by the conserved BH1, BH2, and BH3 domains found in the antiapoptotic Bcl-2 proteins, represented by Bcl-2 and Bcl-xL (37, 38). Mutations in the BH3 domain of several proapoptotic proteins abolished their heterodimerization with antiapoptotic partners and dampened their cell-killing activity (37, 39, 40, 41, 42, 43). In addition, polypeptides containing minimal BH3 domain sequences of Bax and Bak are capable of binding to antiapoptotic proteins (39, 43) and inducing apoptosis in transfected cells or cell-free systems (44). The presence of the conserved BH3 domain in all the BOD variants and the observed loss of cell killing in BOD mutants with alterations in the BH3 domain underscore the importance of this region for apoptosis induction.
It is becoming clear that the proapoptotic Bcl-2 proteins can be divided into two subgroups: one with BH1, BH2, and BH3 domains and one with the BH3 domain only. Although both subgroups could dimerize with antiapoptotic Bcl-2 proteins to regulate apoptosis, all proteins in the first subgroup (Bax, Bak, and Bok) have transmembrane-anchoring regions and could regulate mitochondrial cytochrome c release and the subsequent activation of caspases (27, 28). In contrast, proteins in the second subgroup probably initiate apoptosis mainly through dimerization with antiapoptotic Bcl-2 proteins to antagonize their function. BOD belongs to the second subgroup of proapoptotic Bcl-2 proteins and shows a wide heterodimerization pattern, capable of interacting with diverse antiapoptotic Bcl-2 proteins of mammalian and viral origins. The broad expression and interaction profile of BOD suggests that it could serve as an apoptosis mediator in diverse cell lineages. Among proteins in the second subgroup, BAD is known to function as a cytoplasmic adaptor protein capable of interacting with other upstream signaling molecules in the cytoplasm (30, 31). The soluble proapoptotic BAD protein binds to widely distributed cytoplasmic protein 14–3-3 after phosphorylation of serine residues in its 14–3-3 binding sites (30, 31). Because insulin-like growth factor I and insulin activate the Akt kinase capable of phosphorylating BAD, BAD phosphorylation is an important mechanism by which upstream survival factors suppress apoptosis (42, 45, 46, 47, 48). In contrast, the soluble BID normally locates in the cytoplasm and signals apoptosis by binding to the membrane-bound proapoptotic protein Bax (15). Although the exact role of BOD in apoptosis regulation requires further study, the lack of a channel-forming domain in BOD and its preferential interaction with antiapoptotic Bcl-2 proteins in the yeast two-hybrid assay suggest that BOD, like BAD, may also function as an adaptor protein for upstream signals and promote apoptosis by interacting with antiapoptotic Bcl-2 proteins. Future studies on BOD interaction with upstream cytoplasmic proteins are of interest.
Recently, a proapoptotic protein Bim was identified based on expression
cloning of Bcl-2-binding proteins from a mouse lymphoma cell line (19).
This mouse protein has three splicing variants, all of which contain a
shared C-terminal BH3 domain. Sequence comparison indicated that rat
BOD-L and BOD-M represent the orthologs of Bim-splicing variants Bim-EL
and Bim-S, respectively. However, the BOD gene encodes a shorter
variant (BOD-S) in the rat ovary having only 93 amino acids of the C
terminus of BOD-L, whereas the shortest Bim variants (Bim-S) are 110
amino acids in length. Of interest, both BOD-S and a truncated BOD
construct (BOD-ES), containing only 70 amino acids in the C terminus,
are still capable of inducing apoptosis, consistent with the finding
that the short form of Bim is the most potent isoform in apoptosis
induction after interleukin-3 deprivation or 
-irradiation of a tumor
cell line (19). Although these data suggest that C-terminal sequences,
including the consensus BH3 domain, are important for the proapoptotic
activity of BOD, the N-terminal sequences that are unique to BOD-L and
BOD-M could be important for posttranslational regulation of these BOD
variants. The future isolation of the BOD/Bim gene will
elucidate the splicing mechanisms leading to the derivation of
different mRNA variants.
In contrast to Bim, which does not bind virally derived antiapoptotic
protein E1B 19 k and Epstein-Barr virus (EBV) BHRF-1 in a
coprecipitation test (19), BOD heterodimerizes with all known mammalian
antiapoptotic Bcl-2 proteins and the viral-derived BHRF-1 (Fig. 2). It
is possible that the yeast two-hybrid assay is more sensitive than the
protein coprecipitation test used to study Bim function. In addition,
it has been reported that Bim is colocalized with Bcl-2 and possibly
anchored to membrane fractions through its C-terminal hydrophobic
region (19). However, sequence analysis of BOD indicated that the
hydrophobic sequence in the putative transmembrane region is
exceedingly short, and the importance of this C terminus region
in BOD action requires further study. Because BOD is ubiquitously
expressed in diverse tissues and shows a wide heterodimerization
property, BOD could regulate apoptosis in a wide spectrum of tissues by
interacting with diverse antiapoptotic Bcl-2 proteins.
The present identification of a proapoptotic protein BOD based on its heterodimerization with the antiapoptotic Mcl-1 protein provides further understanding of genes involved in the decision step of ovarian follicle apoptosis. The yeast two-hybrid approach used here and in earlier studies (18, 31) serves as an experimental paradigm to elucidate protein-protein interactions between diverse tissue-specific Bcl-2 protein pairs in the decision of cell fate. In the ovary, the antiapoptotic protein Mcl-1 is believed to heterodimerize with BOD and/or other proapoptotic Bcl-2 proteins (Bax, Bok, and BAD), and the ratio of these protein pairs could regulate downstream events including binding to Apaf-1 or other mammalian Ced-4 homologs and the release of mitochondrial cytochrome c, leading to the activation of caspases as executioners of apoptosis. It is envisioned that further studies on the identification and hormonal regulation of tissue-specific Bcl-2 proteins and their heterodimerization protein partners could unravel intracellular mechanisms underlying apoptosis.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Nucleotide sequences of the putative Bcl-2-related cDNA fragments were used to design primers to prepare a cDNA sublibrary enriched with clones containing the 5'-end sequence of the candidate cDNA. To allow 5'-end extension, RT was performed using rat ovarian mRNA preparations and a specific primer downstream of the termination codon of the putative ORF found in the novel cDNAs. After second-strand synthesis, the enriched cDNA pool was tailed at 5'-ends with adaptor sequences to allow further PCR amplification. The sublibrary was then used as a template for PCR amplification of upstream sequences using internal primer pairs. PCR products were fractionated using agarose gels, and those with strong hybridization signals to the original cDNA fragments were subcloned into the pUC18 vector. After screening of the sublibrary based on colony hybridization using the original cDNA fragment as a probe, clones with extended 5'-end sequences of the putative Bcl-2-related protein were isolated for DNA sequencing. Using this procedure, cDNAs encoding the complete ORF of the BOD and several putative splicing variants were isolated.
Construction of Expression Vectors Encoding BOD Variants and
Mutants
Using Pfu or Vent DNA polymerase, different BOD mutants were
generated by oligonucleotide-directed, two-step PCR mutagenesis (18),
whereas the truncated BOD mutants were derived by PCR amplification
using specific primers. Wild-type and mutant cDNAs were subcloned into
the pGBT9 expression vector for yeast cell studies or into the pcDNA3
expression vector (Invitrogen, Inc., San Diego, CA) for mammalian cell
studies. The authenticity of wild-type and mutant constructs was
confirmed by dideoxy sequencing.
Binding between BOD and Different Bcl-2 Family Members
Interactions between BOD and different Bcl-2 family members were
assessed in yeast cells using the pGBT9 GAL4-binding domain and pGADGH
GAL4-AD vectors. Specific binding of different protein pairs in yeast
was evaluated based on the activation of the GAL1-HIS3 reporter gene.
Wild-type and mutant BOD cDNAs were subcloned in pGBT-9, whereas all
other Bcl-2 related proteins were expressed as Gal-AD fusion proteins
using the pGADGH vector. A minimum of six independent transformants
with each pair of hybrid cDNAs were analyzed for the expression of
GAL1-HIS3 reporter gene. For GAL1-HIS3 reporter expression, cells were
grown in a medium lacking leucine, tryptophan, and histidine but
containing 5–30 mM 3-aminotriazole to inhibit endogenous
histidine production.
Analysis of Apoptosis after Transient Transfection of CHO
Cells
Apoptosis was monitored after transfection of different
cDNAs as previously described (18). Briefly, CHO cells were plated
at a density of 2 x 105 cells per well in DMEM/F12
supplemented with 10% FBS, 100 U/ml penicillin, 100 µg/ml
streptomycin, and 2 mM glutamine. One day later, cells were
transfected using the lipofectamine procedure (Life Technologies,
Gaithersburg, MD) with the empty pcDNA3 expression vector or the same
vector containing different cDNAs, together with 1/20 fractions of an
indicator plasmid pCMV-ß-gal to allow the identification of
transfected cells. Inclusion of 20-fold excess expression vectors as
compared with the pCMV-ß-gal reporter plasmid ensured that most of
the ß-galactosidase-expressing cells also expressed the
protein(s) under investigation. Cells were incubated with plasmids in a
serum-free medium for 12 h, followed by the addition of FBS to a
final concentration of 5%. After an additional culture for 12 h,
cells were fixed by 0.25% glutaraldehyde and stained with X-gal [0.4
mg/ml in buffer containing 150 mM NaCl, 100 mM
Na2HPO4, 1 mM MgCl2,
3.3 mM
K4Fe(CN)6·3H2O, and
3.3 mM K3Fe(CN)6, pH 7.0] for
6 h at 37 C to detect ß-galactosidase expression. The number of
viable blue cells were counted by microscopic examination. Data are
expressed as the percentage (mean ± SEM) of viable
cells as compared with the control group based on the counting of six
independent samples (at least 500 cells per 35-mm dish) from three or
more separate experiments. Statistical differences among treatment
groups were analyzed using one-way ANOVA and Scheffe F-test.
Northern and Southern Blot Analysis
For mRNA analysis, the BOD cDNA probe (nucleotides 1–328 of the
BOD-L ORF) was radiolabeled with 32P using random priming.
Blots containing poly(A)+ RNA from various adult human and rat tissues
(CLONTECH) were hybridized with the BOD probe at 60 C before washing to
a final stringency of 0.1x saline sodium citrate (SSC) and
0.5% SDS at 65 C. To estimate mRNA loading, the blots were
subsequently probed with a ß-actin cDNA probe. For studies of
cross-species conservation of the BOD gene, a Zoo blot (CLONTECH)
containing EcoRI-digested genomic DNA from different
vertebrates was probed with a 32P-labeled cDNA probe
corresponding to the 5'-end sequences of BOD-L (nucleotides -180 to
+40 of BOD-L). The blot was washed to a final stringency of 0.5% SDS
and 0.2x SSC at 55 C before exposure.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This study was supported by NIH Grant HD-31566.
Received for publication April 3, 1998. Revision received May 15, 1998. Accepted for publication May 19, 1998.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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