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Reproductive Biology Unit, Departments of Obstetrics and Gynaecology (J.L., J.-M.K., M.L., B.K.T.), Cellular and Molecular Medicine (J.L., B.K.T.) and Biochemistry (A.E.M., R.G.K.), University of Ottawa; Ottawa Civic Hospital Loeb Research Institute; ApoptoGen and the Solange Gauthier Karsh Molecular Genetics Research Laboratory, Children’s Hospital of Eastern Ontario (P.L., A.E.M., R.G.K.) Ottawa, Ontario, Canada K1Y 4E9
Address all correspondence and requests for reprints to: Dr. Benjamin K. Tsang, Department of Obstetrics and Gynaecology, Ottawa Civic Hospital, 1053 Carling Avenue, Ottawa, Ontario, Canada K1Y 4E9. E-mail: ben{at}civich.ottawa.on.ca
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Inhibitor of apoptosis proteins (IAPs) is a novel family of intracellular proteins that suppress apoptosis induced by a variety of stimuli, including growth factor deprivation, menadione (a potent inducer of free radicals), and transient transfection of pro-interleukin-1ß converting enzyme (9, 10, 11). IAPs were first identified in baculoviruses, where they function to keep the host cell alive, whereas the viruses replicate (12, 13). Four IAPs have been identified in the mammal: neuronal apoptosis inhibitory protein (NAIP,14), X-link inhibitor of apoptosis protein (XIAP, 9; miha, 11; ilp, 10), human inhibitor of apoptosis protein-1 (HIAP-1, 9; cIAP-2, 15; mihc, 11) and human inhibitor of apoptosis protein-2 (HIAP-2, 9; cIAP-1, 15; mihb, 11). With the exception of NAIP, which only has the N-terminal repeats named baculovirus IAP repeats (BIRs), all other mammalian IAPs identified to date possessed both N-terminal BIRs and a C-terminal RING zing finger domain. Although these proteins have been detected in whole ovarian extracts (9), their precise cellular localization and physiologic role in ovarian follicular development and atresia are unknown.
Sufficient gonadotropin support is the most critical survival stimulus for preantral and antral follicles in the process of follicle selection and development (1, 4, 5, 16, 17). We have previously established an in vivo model in which gonadotropin withdrawal by anti-eCG antibody administration rapidly induces apoptosis in small- to medium-size antral follicles, a critical stage of development when atresia is commonly observed (18). This model has provided a valuable tool to examine possible signaling mechanisms and early events associated with the induction of rat granulosa cell apoptosis and follicular atresia. The objective of the present study was to establish the presence of IAPs in rat granulosa and theca cells and to study the role and regulation of IAP expression in follicular development and atresia, using established in vivo models of gonadotropin stimulation and withdrawal. We report the presence of Xiap and Hiap-2 in rat granulosa and theca cells, the expression of which appeared to be developmentally regulated. While the abundance of the IAPs in granulosa cells increased with follicular development to the antral stage, levels of these antiapoptotic proteins were markedly suppressed following the induction of follicular atresia.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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32P]-ddATP (3000 Ci/mmol) were obtained from Amersham
(Arlington Heights, IL). Medium M199 and normal rabbit serum were from
Gibco-BRL (Burlington, Ontario, Canada). 
-probe blotting membrane,
trans-blot supported nitrocellulose membrane, acrylamide
(electrophoresis grade), N,N'-methylene-bis-acrylamide,
ammonium persulfate, tetramethylethylene diamine, DTT, glycine,
SDS-PAGE prestained molecular weight standards (low range), and Bio-Rad
protein assay kit were purchased from Bio-Rad Laboratories (Hercules,
CA). X-ray films were from Eastman Kodak Company (Rochester, NY).
Positively charged slides were from Fisher Scientific (Probe On Plus,
Nepean, Ontario, Canada). The anti-eCG antibody was a gift from Dr. D.
Johnson (University of Kansas, Kansas City, KS). The rabbit polyclonal
anti- Xiap and Hiap-2 antibodies were prepared by immunization with
human Xiap and Hiap-2 GST fusion protein (Korneluk, R. G.,
manuscript in preparation). The PCNA antibody was from Santa Cruz
Biotechnology (Santa Cruz, CA).
Animal preparation
For the assessment of granulosa and theca cell apoptosis and IAP
expression during follicular maturation, different stages of follicular
development was induced in 23- to 24-day-old female Sprague-Dawley rats
(50–60 g, Charles River Canada, Montreal, Quebec, Canada) with DES (1
mg/day, sc, for 3 consecutive days and killed 24 h after last
injection) or eCG (15 IU, ip and killed 48 h thereafter) or eCG
(15 IU, ip) and followed 48 h later with hCG (15 IU, ip and killed
8 h post hCG). These treatments synchronize ovarian follicular
development at predominantly the preantral/early antral, small to
medium sized antral and preovulatory stages, and provide high yields of
granulosa cells that are largely apoptotic, differentiated, and
luteinized, respectively (19, 20). For studies on the induction of
follicular atresia by gonadotropin withdrawal (18), rats at 23–24 days
of age were injected with eCG (15 IU, sc) and 24 h later with
either 100 microliters of either normal (preimmune) rabbit serum or
anti-eCG antiserum (1:10 in saline; ip). Animals were killed 1 or
24 h after normal serum or antiserum injection. While DES
treatment provided predominantly preantral and early antral atretic
follicles (as observed in naturally occurring immature ovaries), this
gonadotropin withdrawal treatment induced atresia at the early antral
and small to medium sized antral stages of development (as found in
ovaries of naturally occurring cycling rats). The animals were fed
prolab RMH 4018 (Agway, Inc., Syracuse, NY) and water ad
libitum. A 14-h light, 10-h dark cycle was maintained with light
cycle initiated at 0600 h. Ovaries were excised for
immunohistochemistry for IAPs and proliferation cell nuclear antigen
(PCNA), and in situ terminal deoxynucleotidyl
transferase-mediated dUTP-biotin end labeling (TUNEL) of apoptotic
cells. In addition, granulosa cells from each group of animals were
harvested by follicle puncture as previously described (20), washed
(900 x g, 10 min), and resuspended in 10
mM HEPES buffer (pH 7.4) containing 1 mM EGTA
and 2 mM PMSF.
In situ localization of apoptotic cells: terminal deoxynucleotidyl
transferase-mediated dUTP-biotin end labeling (TUNEL)
The TUNEL was performed as described previously (21). Briefly,
paraffin-embedded whole ovarian sections (4–5 µm) were mounted on
positively charged slides, deparaffinized, hydrated, and treated with
proteinase-K (10 µg/ml in 20 mM Tris and 2 mM
CaCl2, pH 7.4; 37 C, 30 min) and then washed thoroughly for
15 min in Tris buffer (100 mM Tris and 150 mM
NaCl, pH 7.5), followed by immersion in methanol containing 0.3%
H2O2 (RT, 20 min) to inhibit endogenous
peroxidase activity. After rinsing in distilled water for 15 min, the
sections were soaked in the TdT buffer (25 mM Tris-HCl, 200
mM sodium cacodylate, 5 mM cobalt chloride, 250
µg/ml BSA, pH 6.6, 15 min) and then incubated in 50 µl of TdT
buffer containing 10 U TdT and 1 nmol biotinylated 16-dUTP in a
humidified chamber (37 C, 60 min). The reaction was stopped by soaking
sections in 2 x SSC (300 mM NaCl, 30 mM
sodium citrate), followed by washing in PBS (RT, 15 min). The
biotinylated dUTP molecules incorporated into nuclear DNA were
visualized by incubation with horseradish peroxidase-conjugated
streptavidin (1:100; RT, 30 min). After further washing in PBS (15
min), the sections were immersed for 10 min in 0.05 M
Tris-HCl buffer, pH 7.6, containing 0.3 mg/ml diaminobenzidine
tetrahydrochloride (DAB), 0.65 mg/ml sodium azide, 10 mM
imidazole, and 0.003% H2O2 (peroxidase
coloring reaction). The nuclei were counterstained with 5% methyl
green buffered with 0.1 M veronal acetate, pH 4.0. In the
negative control slides, TdT enzyme or biotinylated 16-dUTP were
omitted in labeling reactions.
Immunohistochemistry
Paraffin embedded whole ovarian sections were incubated for 15
min in 0.3% H2O2 for 20 min and rinsed
thoroughly with PBS (3 x 15 min). The sections were blocked with
1.5% normal goat serum in PBS (room temperature, 1 h) to suppress
nonspecific binding of IgG, and then incubated (RT, 45 min) with rabbit
polyclonal antihuman Xiap, Hiap-2 or PCNA antibodies in 1% blocking
serum in PBS. After washing with PBS (3 x 15 min), the sections
were incubated with biotin-conjugated goat antirabbit IgG
(1:200 in PBS; room temperature, 1 h), followed by
avidin-biotin-peroxidase complex (room temperature, 1 h) from a
Vector ABC Elite Kit. They were again washed with PBS (3 x 15
min) and incubated with DAB solution (2–5 min). The nuclei were
counterstained with hematoxylin. As a negative control, rabbit IgG (1
µg/ml) was applied to primary antibody reaction in this
experiment.
Solubilized cell extracts and immunoblot analysis
Total cell protein extracts were prepared as follow: granulosa
cells were sonicated (8 s/cycle, 3 cycles) on ice in 10 mM
HEPES buffer (pH 7.4) containing 1 mM EGTA and 2
mM PMSF. The sonicates were stored at -20 C until
electrophoretic analyses were performed. Protein concentration was
determined by the Bio-Rad protein assay.
Equal amount of proteins (60–80 µg, depending on individual experiments) present in cell extracts were resolved by one-dimensional SDS-PAGE (SDS-PAGE), and electrophoretically transferred to nitrocellulose membrane. Membranes were blocked with 5% nonfat milk and subsequently incubated with polyclonal human Xiap and Hiap-2 antibody diluted in TBS (10 mM Tris-buffered saline, pH 7.5) containing 5% milk. An ECL kit was used to visualize immunopositive protein.
DNA fragmentation analysis
DNA was extracted and labeled as previously described (22). To
3'-end label DNA, 1 µg of DNA was incubated with 25 U terminal
deoxynucleotidyl transferase (TdT) and 5 µCi
[32P]-ddATP (3000 Ci/mmol) in 50 µl of 200
mM sodium cacodylate, 5 mM cobalt chloride, 250
µg/ml BSA, 25 mM Tris-HCl (pH 6.6, 37 C, 60 min) and the
reaction was terminated by the addition of 5 µl of 250 mM
EDTA (pH 8.0). Unincorporated radionucleotide in the reactions were
removed by the addition of 0.2 x volume 10 M ammonium
acetate and 3 x volume ice-cold 100% ethanol, followed by
incubation with 50 µg yeast tRNA (-70 C, 60 min). The nucleic acid
was collected by centrifugation (14,000 x g; 4 C, 20
min), resuspended in buffer and reprecipitated with ethanol. The DNA
was again pelleted by centrifugation, washed with 0.25 ml ice-cold 80%
ethanol, and allowed to air dry. Samples were resuspended in TE buffer.
The labeled samples were resolved by 1.8% agarose gel electrophoresis.
The gel was dried (3 h) and exposed to a Bio-Rad phosphoimager screen
to densitometrically quantify low molecular weight DNA (<4 Kb) and
subsequently to x-ray film at -80 C.
Statistical analysis
Results were expressed as the mean ± SEM of
three to five experiments. Statistical analysis were carried out by
one- or two-way ANOVA. Significant differences between treatment groups
were determined by the Tukey test. Statistical significance was
inferred at P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Consistent with the concept that IAPs
are intracellular proteins (11, 23), Xiap and Hiap-2 were found in the
cytoplasm and nuclei of granulosa cells from healthy follicles (Fig. 2, c and e). In situ TUNEL and
immunohistochemistry for PCNA (an auxiliary protein of DNA polymerase
highly expressed at G1/S interphase) performed to study if and how
Xiap and Hiap-2 expression relates to granulosa cell apoptosis and
proliferation during follicular development and atresia indicates that
Hiap-2 and Xiap were expressed in both granulosa and theca cells in
healthy follicles (TUNEL negative; Fig. 1, a–c), whereas they were
proliferatively most active (PCNA positive: Fig. 1, e–g). As
summarized in Table 1, Xiap and Hiap-2
were less abundant in granulosa cells from preantral ["H" (Fig. 1a)] and early antral ["A" and "H" (Fig. 1, a and b)]
follicles where follicular atresia is frequently observed (Fig. 1, i,
j, k, l, m, n, o, and p). Consistent with our present findings (Fig. 1, a–d) and those of others (6, 18, 24, 25) that granulosa but not theca
cells undergo apoptosis, Xiap and Hiap-2 expression were greater in
theca than in granulosa cells from preantral, early antral, and antral
follicles (Fig. 1, i, j, k, l, m, n, o, and p). Oocytes (Fig. 1, k and
o) and ovarian surface epithelial cells (Fig. 1, l and p) also stained
positively for Xiap and Hiap-2.
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). Compared with those from healthy follicles, granulosa
cell PCNA staining intensity in these follicles at the preantral and
early antral stages was low (Fig. 1, e and f). However, granulosa cell
proliferation was most active in healthy, small-to-medium sized antral
follicles, as indicated by intense PCNA staining (Fig. 1g). PCNA
protein expression decreased dramatically in atretic follicle at this
stage of development, confirming the well established notion that
follicular atresia is accompanied by decreased granulosa cell
proliferation (Fig. 1, g and h). Although parts (right side)
of the atretic antral follicle (Fig. 1g) appeared somewhat stained for
PCNA, close examination at higher magnification demonstrated that, in
contrast to that in healthy follicles where PCNA was nucleus-specific,
this might be antifactual as the heavy immunostraining of this atretic
follicle was localized outside the nuclei (Fig. 2, a and b). Similar
developmental patterns were observed in granulosa cell IAP expression,
where significant decrease in Xiap (Fig. 1, m, n, o, and p) and Hiap-2
(Fig. 1, i, j, k, and l) abundance was only evident in atretic
follicles at the mid to late antral stages, suggesting a decrease in
IAP expression may be associated with atresia in this follicle stage.
In addition, there was a change in the intracellular distribution of
IAPs in granulosa cells with the induction of atresia. Whereas
granulosa cells from healthy antral follicles exhibited more intense
Hiap-2 immunoreactivity in the nuclei than the cytoplasm, this IAP was
predominantly localized in the extra-nuclear portion of the dying cells
(detached from follicular wall) in atretic follicles (Fig. 2, c and d).
Although the intracellular localization of Xiap in the healthy
follicles was similar to that of Hiap-2, a relatively higher proportion
of Xiap immunoreactivity in granulosa cells of atretic follicles
appeared to be present in the cytoplasm than in the nuclei (Fig. 2, e
and f). Interestingly, compared with healthy follicles, a decrease in
theca cell IAP expression observed in atretic follicles (Fig. 1, k, l,
o, and p) was accompanied by decreased PCNA immunoreactivity
irrespective of follicular maturation (Fig. 1, e, f, g, and h; Table 1).
Further experiments were performed to confirm the results from
immunohistochemistry and determine quantitatively whether granulosa
cell IAP expression may be inversely related to apoptosis. Granulosa
cells were isolated from follicles in DES-treated (preantral and early
antral stages), eCG-treated (mid to late antral stages), and
hCG-treated (preovulatory stage) treated rats. IAP expression and DNA
fragmentation were analyzed by Western blot and 3'-end DNA
labeling/agarose gel electrophoresis, respectively. As shown in Fig. 3, A and B, granulosa cell Hiap-2 (68
kDa) expression was minimal in the preantral and early antral stages of
follicular development and increased with follicular maturation
(P < 0.05). A similar pattern of developmental
expression was also observed for Xiap (55 kDa), although the difference
between the stages failed to meet statistical significance
(P > 0.05; Fig. 3D). IAP expression was inversely
correlated with granulsoa cell DNA fragmentation (Fig. 3, E and F).
Apoptosis was most evident in the DES group when Hiap-2 abundance was
lowest (Fig. 3, B and F).
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, Hiap-2 and Xiap expression was induced
by eCG in vivo in a time-dependent manner (Fig. 4, A–D).
Withdrawal of gonadotropin support in the eCG-primed animals with an
anti-eCG antibody markedly suppressed Hiap-2 (Fig. 4, A and B) and Xiap
(Fig. 4, C and D) expression at 24 h, compared with respective
controls. These responses were accompanied by a marked increase in
granulosa cell apoptosis as evident by the appearance of extensive
(8-fold increase) DNA fragmentation in the antibody group compared with
its respective control (Fig. 4, E and F).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The recent identification of the IAP family of intracellular proteins have opened a new field of research into the molecular mechanism of apoptosis. This communication represents the first report on the cellular localization and regulation of IAP expression in the ovary. The finding that granulosa cell Xiap and Hiap-2 expression were low in preantral and early antral follicles and increased with follicular maturation is consistent with the notion that fate of these follicles (ovulation vs. atresia) is determined during these stages of the development. It is possible that IAP expression at these stages is maintained at a minimum level so as to readily afford granulosa cell apoptosis and thus follicular atresia upon receipt of an appropriate cell death stimulus. In the present study, treatment immature rats with DES markedly suppressed Hiap-2 and Xiap protein content and significantly induced apoptotic DNA fragmentation in granulosa cells of preantral follicles. The influence of estrogen on granulosa cell apoptosis is complex and appears to depend on not only the nature of the estrogenic compound, but also on the duration and the mode of administration (29, 30). It has been demonstrated that apoptosis occurs in the preantral follicles of DES-treated rat after DES withdrawal, and this cell death process could be prevented with DES replenishment (30). However, others reported that continuous DES administration also induced widespread atresia in the rat ovaries (31). Irrespective of the mechanism(s) involved, it is of interest to note that, compared with those from eCG and eCG + hCG-treated group, the significantly more extensive apoptotic DNA degradation (>20-fold) in DES-treated group was associated with a considerable lower Hiap-2 and Xiap abundance (approximately 5% and 60%, respectively). These data further suggest that the low IAP expression in the early stages of follicular development may be an important determinant in atresia at this follicle stage.
Previous studies have demonstrated that gonadotropins suppress granulosa cell apoptosis in preovulatory follicles and in isolated cell conditions in vitro (1, 4, 5, 16, 17). In vivo experiments have also confirmed that follicles destined for atresia can be rescued at an early phase by exogenous gonadotropins (31, 32), suggesting that FSH (and/or LH) is an important antiapoptogenic factor in addition to its established role in follicular development. We have demonstrated here that eCG induced Xiap and Hiap-2 expression and suppressed granulosa cell apoptosis in vivo. Withdrawal of gonadotropin support attenuated the eCG-induced granulosa cell IAP expression and markedly increased apoptotic DNA fragmentation in early antral and antral follicles. Our results raise the interesting possibility that induction of IAP expression may be an important mechanism underlying the antiatretogenic action of gonadotropin in the ovary. In addition, the current demonstration that whereas Hiap-2 and Xiap are mainly localized in the nuclei of granulosa cells from healthy follicles, the induction of granulosa cell apoptosis during follicular atresia appeared to be associated with a change in the intracellular distribution of these protein, with predominant localization being in the cytoplasm. The physiologic significant of these changes is unknown.
The signaling pathway for eCG for the up-regulation of granulosa cell IAP expression is unknown. In addition to its FSH activity, eCG also contains a low LH activity component. Binding of gonadotropins to their granulosa cell membrane receptors activates the protein kinase A (PKA) pathway (33). In addition, it has been also demonstrated that the antiatretogenic action of FSH is partially mediated through local production of IGF-I and activation of the IGF-receptor/tyrosine kinase pathway (34). It would be of interest to determine whether the up-regulation of Hiap-2 and Xiap expression by gonadotropins is a direct action via the PKA pathway or through indirect mechanism(s), such as the IGF signaling system.
In the ovary, as in other cell systems, cell death inducers (e.g. Fas) and survival factors [e.g. Bcl-xL and IAP (present study)] are constitutively present (35, 36, 37, 38) and the fate of the granulosa cell (survival vs. apoptosis) is determined by the balance of these opposing activities. The survival of granulosa cells in follicles that escape atresia and selected to ovulate in each reproductive cycle may occur through up-regulation of the survival factors and/or removal of the cell death inducers by an appropriate stimuli. It is possible that by inducing Hiap-2 and Xiap overexpression in granulosa cells, FSH is able to tilt the balance toward cell survival, and thus follicular growth and ovulation. Alternatively, preliminary studies from our laboratory have demonstrated that whereas gonadotropin suppressed granulosa cell Fas and Fas ligand expression in antral and preovulatory follicles in immature rats, gonadotropin withdrawal by treatment of the eCG-primed animals with anti-eCG antiserum (as in the present studies) resulted in the overexpression of these cell death factors and induced follicular atresia (36). The relative importance of these cellular changes and the interactions of their pathways in the induction of granulosa cell apoptosis remains to be determined.
Apoptosis in atretic follicles in most mammals studied to date are confined to granulosa cells (3, 18, 24, 26). Consistent with these findings is our observation that, irrespective of the stage of follicular maturation, theca cells in all atretic follicles were TUNEL-negative. Interestingly, Xiap and Hiap-2 were highly expressed in theca cells, and their immunoreactivities in preantral and early antral follicles were much higher than those in granulosa cells. This phenomenon may be one of the mechanisms in place to prevent theca cells from undergoing apoptosis. Alternatively, IAPs may be involved in other as yet undetermined physiological process such as theca cell differentiation. The reason(s) for the decrease of IAP expression in theca cells of atretic follicles is not known.
The mechanism (s) by which IAPs interact with established cell death
pathways to regulate apoptosis is poorly understood. Recent studies
reported that Hiap-2 is able to interact with signaling component of
both tumor necrosis factor (TNF) receptor I and II (TNFR1 and TNFR2)
pathways (15, 39). While TNFR1 signals mainly for cytotoxicity (40),
TNFR2 has been implicated in cell proliferation or survival (41). Using
biochemical purification and subsequent molecular cloning method,
Hiap-2 has been shown to be a component of the of the TNFR2 signaling
complex, in which the BIR motif-containing domain interacts with TRAF2
(15). TRAF1 and TRAF2 have been shown to interact with a region within
the cytoplasmic domain of TNFR2 required for signal transduction (42).
Another report has indicated that Hiap-2 is one of the component of the
"survival complex" consisting of Hiap-2, TRAF2, and the
TNFR1-associated death domain protein (TRADD), and that this complex is
formed before TNFR1 stimulation (40). Precisely how Hiap-2 modulate the
multiple and overlapping signal transduction pathways of the two TNF
receptor subtype is unknown. The possibility that Hiap-2 may be
inhibitory in one (TNFR1) and stimulatory in another (TNFR2) is
intriguing and cannot be excluded. In the latter context, recent study
by Lee et al.(43) has suggested that human IAPs, via
interaction with TRAF2, facilitate TNF-induced cell proliferation.
In our study, Hiap-2 expression was higher in follicles where granulosa
and theca cells were proliferatively active (PCNA positive), thus also
raising the possibility that Hiap-2 could play a role in the regulation
of follicular cell proliferation in the ovary. Whether this indeed is
the case awaits further investigation.
Moreover, recent study by Daveraux et al. (44) has demonstrated that Xiap inhibits caspase-3, a "cell death" protease downstream on the TNFR1 pathway, and suppresses apoptosis. Interestingly, granulosa cells from ovarian atretic follicles induced by eCG withdrawal exhibited considerably higher caspase-3 immunoactivity compared with those from healthy ones (Boone, D. L. and B. K. Tsang, unpublished data). It is thus possible that, in addition to its up-regulation during the induction of granulosa cell apoptosis by gonadotropin withdrawal, caspase-3 may be an additional point of regulation by IAP. Whether these regulatory mechanisms exist for the antiapoptotic action of gonadotropin in the ovary remains to be determined.
In summary, Xiap and Hiap-2 are expressed in rat granulosa and theca cells during follicular development, and the abundance of IAPs in granulosa cells is regulated during follicular development and atresia in an antiapoptotic fashion. IAPs appear to be an intracellular protein family important in the "life" and "death" decision of granulosa cells during follicular selection and may play a critical role as a cell survival factor in the control of stage-specific follicular atresia during development.
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Footnotes |
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2 Recipient of a Genesis Research Foundation Graduate Studentship and
an Ontario Graduate Scholarship.
Received August 7, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B by TNFR2 and CD40. Science 269:1424–1427B activation. J Exp Med 185:1275–1285This article has been cited by other articles:
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 C. Tamanini, G. Basini, F. Grasselli, and M. Tirelli Nitric oxide and the ovary J Anim Sci, February 1, 2003; 81(14_suppl_2): E1 - 7. [Abstract] [Full Text] [PDF]
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 T. Hasegawa, K. Suzuki, C. Sakamoto, K. Ohta, S. Nishiki, M. Hino, N. Tatsumi, and S. Kitagawa Expression of the inhibitor of apoptosis (IAP) family members in human neutrophils: up-regulation of cIAP2 by granulocyte colony-stimulating factor and overexpression of cIAP2 in chronic neutrophilic leukemia Blood, February 1, 2003; 101(3): 1164 - 1171. [Abstract] [Full Text] [PDF]
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 D. J. Kominsky, R. J. Bickel, and K. L. Tyler Reovirus-Induced Apoptosis Requires Mitochondrial Release of Smac/DIABLO and Involves Reduction of Cellular Inhibitor of Apoptosis Protein Levels J. Virol., October 11, 2002; 76(22): 11414 - 11424. [Abstract] [Full Text] [PDF]
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C. Wu Xiao, E. Asselin, and B. K. Tsang Nuclear Factor {kappa}B-Mediated Induction of Flice-Like Inhibitory Protein Prevents Tumor Necrosis Factor {alpha}-Induced Apoptosis in Rat Granulosa Cells Biol Reprod, August 1, 2002; 67(2): 436 - 441. [Abstract] [Full Text] [PDF]
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Y. Wang, S. Chan, and B. K. Tsang Involvement of Inhibitory Nuclear Factor-{kappa}B (NF{kappa}B)-Independent NF{kappa}B Activation in the Gonadotropic Regulation of X-Linked Inhibitor of Apoptosis Expression during Ovarian Follicular Development in Vitro Endocrinology, July 1, 2002; 143(7): 2732 - 2740. [Abstract] [Full Text] [PDF]
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Y. Wang, E. Asselin, and B. K. Tsang Involvement of Transforming Growth Factor {alpha} in the Regulation of Rat Ovarian X-Linked Inhibitor of Apoptosis Protein Expression and Follicular Growth by Follicle-Stimulating Hormone Biol Reprod, June 1, 2002; 66(6): 1672 - 1680. [Abstract] [Full Text] [PDF]
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S.-Y. Chun, H.-W. Bae, W.-J. Kim, J.-H. Park, S. Y. Hsu, and A. J. W. Hsueh Expression of Messenger Ribonucleic Acid for the Antiapoptosis Gene P11 in the Rat Ovary: Gonadotropin Stimulation in Granulosa Cells of Preovulatory Follicles Endocrinology, June 1, 2001; 142(6): 2311 - 2317. [Abstract] [Full Text] [PDF]
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E. Asselin, Y. Wang, and B. K. Tsang X-Linked Inhibitor of Apoptosis Protein Activates the Phosphatidylinositol 3-Kinase/Akt Pathway in Rat Granulosa Cells during Follicular Development Endocrinology, June 1, 2001; 142(6): 2451 - 2457. [Abstract] [Full Text] [PDF]
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C. W. Xiao, K. Ash, and B. K. Tsang Nuclear Factor-{{kappa}}B-Mediated X-Linked Inhibitor of Apoptosis Protein Expression Prevents Rat Granulosa Cells from Tumor Necrosis Factor {{alpha}}-Induced Apoptosis Endocrinology, February 1, 2001; 142(2): 557 - 563. [Abstract] [Full Text] [PDF]
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R. Sasson, K. Tajima, and A. Amsterdam Glucocorticoids Protect against Apoptosis Induced by Serum Deprivation, Cyclic Adenosine 3',5'-Monophosphate and p53 Activation in Immortalized Human Granulosa Cells: Involvement of Bcl-2 Endocrinology, February 1, 2001; 142(2): 802 - 811. [Abstract] [Full Text] [PDF]
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C.-L. Hu, R. G. Cowan, R. M. Harman, D. A. Porter, and S. M. Quirk Apoptosis of Bovine Granulosa Cells After Serum Withdrawal Is Mediated by Fas Antigen (CD95) and Fas Ligand Biol Reprod, February 1, 2001; 64(2): 518 - 526. [Abstract] [Full Text]
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J. Li, Q. Feng, J.-M. Kim, D. Schneiderman, P. Liston, M. Li, B. Vanderhyden, W. Faught, M. F. K. Fung, M. Senterman, et al. Human Ovarian Cancer and Cisplatin Resistance: Possible Role of Inhibitor of Apoptosis Proteins Endocrinology, January 1, 2001; 142(1): 370 - 380. [Abstract] [Full Text] [PDF]
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 A. L.L. Durlinger, P. Kramer, B. Karels, J.A. Grootegoed, J. Th.J. Uilenbroek, and A. P.N. Themmen Apoptotic and proliferative changes during induced atresia of pre-ovulatory follicles in the rat Hum. Reprod., December 1, 2000; 15(12): 2504 - 2511. [Abstract] [Full Text] [PDF]
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N. A. Cataldo, D. A. Dumesic, P. C. Goldsmith, and R. B. Jaffe Immunolocalization of Fas and Fas ligand in the ovaries of women with polycystic ovary syndrome: relationship to apoptosis Hum. Reprod., September 1, 2000; 15(9): 1889 - 1897. [Abstract] [Full Text] [PDF]
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S. M. Quirk, R. M. Harman, S. C. Huber, and R. G. Cowan Responsiveness of Mouse Corpora Luteal Cells to Fas Antigen (CD95)-Mediated Apoptosis Biol Reprod, July 1, 2000; 63(1): 49 - 56. [Abstract] [Full Text]
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 S. Y. Hsu and A. J. W. Hsueh Tissue-Specific Bcl-2 Protein Partners in Apoptosis: An Ovarian Paradigm Physiol Rev, April 1, 2000; 80(2): 593 - 614. [Abstract] [Full Text] [PDF]
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S. L. Vickers, R. G. Cowan, R. M. Harman, D. A. Porter, and S. M. Quirk Expression and Activity of the Fas Antigen in Bovine Ovarian Follicle Cells Biol Reprod, January 1, 2000; 62(1): 54 - 61. [Abstract] [Full Text]
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D. A. Porter, S. L. Vickers, R. G. Cowan, S. C. Huber, and S. M. Quirk Expression and Function of Fas Antigen Vary in Bovine Granulosa and Theca Cells During Ovarian Follicular Development and Atresia Biol Reprod, January 1, 2000; 62(1): 62 - 66. [Abstract] [Full Text]
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C. P. Leo, S. Y. Hsu, S.-Y. Chun, H.-W. Bae, and A. J. W. Hsueh Characterization of the Antiapoptotic Bcl-2 Family Member Myeloid Cell Leukemia-1 (Mcl-1) and the Stimulation of Its Message by Gonadotropins in the Rat Ovary Endocrinology, December 1, 1999; 140(12): 5469 - 5477. [Abstract] [Full Text]
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D. Xu, Y. Bureau, D. C. McIntyre, D. W. Nicholson, P. Liston, Y. Zhu, W. G. Fong, S. J. Crocker, R. G. Korneluk, and G. S. Robertson Attenuation of Ischemia-Induced Cellular and Behavioral Deficits by X Chromosome-Linked Inhibitor of Apoptosis Protein Overexpression in the Rat Hippocampus J. Neurosci., June 15, 1999; 19(12): 5026 - 5033. [Abstract] [Full Text] [PDF]
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J.-M. Kim, Y.-D. Yoon, and B. K. Tsang Involvement of the Fas/Fas Ligand System in p53-Mediated Granulosa Cell Apoptosis during Follicular Development and Atresia Endocrinology, May 1, 1999; 140(5): 2307 - 2317. [Abstract] [Full Text]
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 Q. L. Deveraux and J. C. Reed IAP family proteins---suppressors of apoptosis Genes & Dev., February 1, 1999; 13(3): 239 - 252. [Full Text]
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S. M. Quirk, D. A. Porter, S. C. Huber, and R. G. Cowan Potentiation of Fas-Mediated Apoptosis of Murine Granulosa Cells by Interferon-{gamma}, Tumor Necrosis Factor-{alpha}, and Cycloheximide Endocrinology, December 1, 1998; 139(12): 4860 - 4869. [Abstract] [Full Text] [PDF]
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