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Original Studies |
Department of Bacteriology and Immunology, Haartman Institute (M.P.E.L., O.R.), Children’s Hospital (M.A., I.K., M.H.), and Department of Obstetrics and Gynecology and Pathology (R.B.), University of Helsinki and Programme for Developmental and Reproductive Biology, Biomedicum (M.P.E.L., M.A., I.K., O.R., M.H.), 00290 Helsinki, Finland; and Departments of Pediatrics (D.B.W., M.H.) and Molecular Biology and Pharmacology (D.B.W.), Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, Missouri 63110
Address correspondence and requests for reprints to: Markku Heikinheimo, M.D., Ph.D., Children’s Hospital, University of Helsinki, Stenbäckinkatu 11, 00290 Helsinki, Finland. E-mail: markku.heikinheimo{at}helsinki.fi
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Within the endocrine system, GATA-4 and/or GATA-6 are expressed in
hypothalamus (15, 16), pituitary (Heikinheimo et
al., unpublished observations), the female and male gonads
(6, 8, 17, 18, 19, 20, 21), and adrenal gland (22). In
the mouse ovary GATA-4 is expressed in granulosa cells of primary,
secondary, and antral follicles. GATA-4 transcripts are detected in
lesser amounts in theca cells and interstitial cells. In contrast,
GATA-6 messenger RNA (mRNA) is expressed only in granulosa cells of
late antral follicles, preovulatory follicles, and in corpus luteum
(19). Exogenous gonadotropins and estrogens regulate
GATA-4 and -6 transcript levels in murine ovaries in vivo
(18). Recent studies show that GATA-4 is able to regulate
both anti-Müllerian hormone (AMH) and inhibin-
gene
transcription in vitro (20, 21, 22, 23, 24).
The transcriptional activity of the GATA proteins is modulated through interactions with other transcription factors and transcriptional coactivators/repressors. For example, GATA-1 interacts with a zinc finger protein termed "Friend of GATA-1" (FOG-1) (25). This interaction is critical for the function of GATA-1 in erythropoiesis and megakaryopoiesis (26, 27). Recently, another novel regulatory cofactor for GATA family members, designated FOG-related factor (FOG-2), was identified (28, 29, 30, 31). In the mouse and human, FOG-2 is expressed abundantly in heart, brain, and testis but the expression of this factor in the ovary has not been described (24, 25, 26, 27). FOG-2 is able to interact with all the six known GATA family members by binding to their N-terminal zinc finger (28, 29, 30, 31). Interaction of GATA-4 and FOG-2 leads to modulation of transcriptional activity of GATA-4 that can be either stimulatory or repressive, depending on the specific promoter and the cell type (29, 30, 31).
Because earlier studies have indicated distinct expression patterns and regulation of GATA-4 and GATA-6 in the mouse ovary, we have used human ovarian tissue, primary cultures of human granulosa-luteal (GL) cells, and sex cord tumor specimens to examine the expression and regulation of GATA-4, GATA-6 and FOG-2 in the normal and neoplastic human ovarian cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Normal human ovarian tissue samples (n = 4) were obtained from women (<35 yr of age) whose ovaries were removed because of cervical cancer without preoperative irradiation. Tumor samples were obtained from 24 women who underwent surgery for either granulosa (n = 15) or theca cell tumors (n = 9) at the Department of Obstetrics and Gynecology, Helsinki University Central Hospital. For RNA extraction the specimens were snap-frozen immediately after surgery. For histological analyses and immunohistochemistry the oophorectomy samples and tumor tissue were formalin fixed and paraffin embedded. Clinical stage was determined according to the classification scheme of International Federation of Gynecologists and Obstetricians, and all the specimens were reviewed by the same pathologist (R.B.). The ages of patients with granulosa and theca cell tumors were between 30 and 76 yr (mean, 48) and between 42 and 66 yr (mean, 52), respectively. Eleven of the granulosa cell tumors were stage I, two stage II, one stage III, and one stage IV. All the thecomas were benign and unilateral.
Cell culture
Human GL cells were obtained by follicular aspiration from regularly menstruating women undergoing oocyte retrieval for in vitro fertilization because of either tubal obstruction or infertility of the spouse. Ovarian stimulation was induced by combining a GnRH analog (Suprecur, Hoechst, Frankfurt am Main, Germany) and human menopausal gonadotropin (Pergonal, Serono Nordic, Vantaa, Finland; or Humegon, Organon, Oss, The Netherlands). Oocyte retrieval was carried out 36–37 h after human CG (hCG) (Profasi, Serono; or Pregnyl, Organon) administration at a total dose of 10,000 IU. For each experiment, the cells obtained the same morning from two to four patients were pooled, enzymatically dispersed, and separated from red blood cells by centrifugation through Ficoll-Paque (Pharmacia, Uppsala, Sweden), as described previously (32). Thereafter the cells were directly recovered for RNA extraction or plated at a density of 2–5 x 105 cells/well on 35-mm 6-well dishes (Costar, Cambridge, MA) and cultured in DMEM supplemented with 10% FCS, 2 mM L-glutamine, and antibiotics (Life Technologies, Inc., Grand Island, NY) at 37 C in a 95% air-5% CO2-humidified environment. Cell culture media were changed every other day, and hormone treatments were performed between days 3 and 7 of culture for different time periods.
Hormonal treatments of cultured human GL cells
Before hormone treatment, the cells were transferred to DMEM supplemented with 2.5% FCS. The cells were treated with 30 ng/mL recombinant human FSH (Org 32489; Organon International BV) (33), 30 or 100 ng/mL purified hCG (CR-127; obtained from the National Hormone and Pituitary Distribution Program, NIDDK, NIH, Bethesda, MD), or 0.5–1.0 mM 8-bromo-cAMP (8-Br-cAMP) (Sigma, St. Louis, MO) for indicated time periods at days 3–7 of culture. The time-dependence studies were performed at days 5–7 of culture. Each experiment was performed at least three times with duplicate or triplicate cultures.
RNA extraction and Northern blotting
Total RNA from human ovaries, ovarian tumor samples, or freshly isolated GL cells and cytoplasmic RNA from cultured GL cells were extracted with the guanidine isothiocyanate-cesium chloride method (34) and by the modified NP-40 lysis procedure (35), respectively. RNA was quantified by absorbance at 260 nm. For Northern blots 8 µg RNA from human ovaries, 15 µg RNA from tumor samples, 17–20 µg RNA from freshly isolated human GL cells, and 11 µg RNA from cultured GL cells were size-fractionated in 1.5% agarose gels and transferred to Hybond-N nylon membranes (Amersham International, Aylesbury, Buckinghamshire, UK). For dot blots, 0.6–2 µg cytoplasmic RNA were denatured in 7.5% formaldehyde and 6x SSC [1x SSC = 0.15 M NaCl, 0.015 M Na citrate (pH 7.0)] at 50 C for 30 min and spotted onto nylon membranes using a 96-well Minifold device (Schleicher and Schuell, Keene, NH). The filters were baked for 1 h at 80 C and UV-cross-linked with a Reprostar II ultraviolet illuminator (Camag, Muttenz, Switzerland) for 6 min before hybridization.
RT-PCR, Southern blotting, cDNA cloning, and analysis of cDNAs
A 342-bp human FOG-2 cDNA was synthesized by RT-PCR (36) from human GL cell RNA using oligonucleotides 5'-CAG-AGT-CGA-CAG-CAA-CTT-CC and 5'-GCC-TGC-TGG-ACT-CAA-TTC-AG, designed according to a human FOG-2 EST sequence (GenBank accession no. AA975109). RT reactions were performed as described previously (32), and the cycling conditions for PCR were: 95 C for 30 sec, 58 C for 45 sec, and 72 C for 90 sec with 40 cycles, followed by a final extension of 15 min in 72 C. Southern blot for the amplified FOG-2 cDNA fragment was prepared as described previously (37). The human FOG-2 cDNA was subcloned into the pGEM-T Easy vector (Promega, Madison, WI) and sequenced with an ABI PRISM 377 DNA sequencer (Perkin-Elmer Corp., Applied Biosystems, Foster City, CA). Similarly, human 575-bp GATA-4 and 712-bp GATA-6 cDNAs for in situ hybridization were synthesized from human GL cell RNA by RT-PCR using the following oligonucleotides: 5'-CTC-CTT-CAG-GCA-GTG-AGA-GC and 5'-GAG-ATG-CAG-TGT-GCT-CGT-GC for GATA-4 (GenBank accession no. NM002052) and 5'-ATG-ACT-CCA-ACT-TCC-ACC-TCT and 5'-CAG-CCT-CCA-GAG-ATG- TGT-AC for GATA-6 (GenBank accession no. NM005257). The details of these procedures are described elsewhere; the control in situ hybridization studies with the corresponding riboprobes showed positive and specific labeling in human heart (Kiiveri et al., manuscript in preparation).
In situ hybridization
Human ovarian samples were washed briefly in phosphate-buffered saline, fixed in 4% paraformaldehyde in phosphate-buffered saline, and embedded in paraffin. The sections were subjected to in situ hybridization for human GATA-4, GATA-6, and FOG-2 riboprobes obtained from the cDNAs described above. Tissue sections were incubated with 1 x 106 CPM of [33P]-labeled (1000–3000 Ci/mmol; Amersham, Life Technologies, Arlington Heights, IL) antisense or sense riboprobe in a total volume of 80 µl following the in situ protocol described in detail elsewhere (19, 38).
Labeling of cDNA probes and filter hybridizations
As probes for filter hybridizations we used a human GATA-4
(39), mouse GATA-6 (19), and human FOG-2
(described above) cDNAs. Mouse probe for GATA-6 was used in these
experiments because it gave the lowest background hybridization from
different GATA-6 probes used in our preliminary experiments. Human
cyclophilin (40) or rat glyceraldehyde-6-phosphate
dehydrogenase (41) cDNAs were used as controls for even
loading in the filter hybridizations. All the cDNA inserts were labeled
with [32P]--deoxy-CTP (3000 Ci/mmol; Amersham) and a
Prime-a-gene kit (Promega). The probes were purified with Nick columns
(Pharmacia) and used at 1–3 x 106 dpm/ml in
hybridization solution containing 50% formamide, 6x SSC, 0.1%
Ficoll, 0.1% polyvinylpyrrolidone, 0.1% BSA, 100 µg/mL salmon sperm
DNA, 100 µg/mL yeast RNA, and 0.5% SDS. Dot, Northern, and Southern
blots were hybridized for 16 h at 42 C and washed three times for
20 min with 1x SSC-0.1% SDS at 50 C. Filters were exposed to Fuji RX
x-ray film (Fuji, Tokyo, Japan) with Trimax 16T intensifying screens
(3M, Ferrania, Italy) at -70 C. Alternatively the Northern blots and
the relative densities of dot blot hybridization signals were analyzed
using Fujifilm IP-Reader Bio-Imaging Analyzer BAS 1500 (Fuji Photo Co.
Ltd., Tokyo, Japan) with the MacBas software supplied by the
manufacturer using a Macintosh (Apple Computer Inc., Cupertino, CA)
personal computer.
Analysis of the RNA data
For single comparisons between untreated and hormone-stimulated cultures, the data were analyzed by the Student’s t test using the Exstatics program (Select Micro Systems Inc., Yorktown Heights, NY) on a Macintosh (Apple Computer Inc.) personal computer. The figures represent the mean ± SEM of the values of the duplicate or triplicate cultures, respectively, as expressed in arbitrary densitometric units, and adjusted to a value of 1.0 for the mean of the first control culture.
Immunohistochemistry
Paraffin-embedded human tissue samples were fixed in 4% paraformaldehyde and subjected to immunohistochemistry using a goat polyclonal antimouse GATA-4 IgG (Santa Cruz Biotechnology, Santa Cruz, CA) or nonimmune IgG as the primary antibody (7). A commercially available avidin-biotin immunoperoxidase system was used to visualize bound antibody (Vectastain Elite ABC Kit; Vector Laboratories, Burlingame, CA). 3-Amino-9-ethylcarbazole (Sigma) was used as the chromogen, and the development reaction occurred in the presence of 0.03% H2O2.
Ethical considerations
All tissue samples were collected by approval of the local ethics committee at The Department of Obstetrics and Gynecology, University of Helsinki.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RNA analysis and immunohistochemistry were used to examine
the expression of GATA-4, GATA-6, and FOG-2 in normal human. First, we
studied normal human ovarian samples by in situ
hybridization. These studies revealed abundant GATA-4 mRNA expression
in granulosa cells, but in a lesser amount also in the theca and
stromal cells, and in the luteal glands (Fig. 1
, A and B). GATA-6 mRNA was present also
in granulosa cell layer of the antral follicle, in the luteal glands,
and in minute amounts in the surrounding theca cells. (Fig. 1, C and
D). GATA-6 was also diffusively expressed in the stromal cells, but to
a lesser extent than GATA-4. We could not detect FOG-2 mRNA in
the normal ovarian samples studied. Control in situ
hybridization experiments with corresponding sense probes revealed only
background labeling. Northern blot analysis was used to verify the
results obtained in in situ hybridization experiments. Both
GATA-4 and GATA-6 mRNAs were readily expressed in human ovary samples,
whereas FOG-2 transcripts were only faintly detectable (data not
shown). Specific hybridization signals were detected for all the three
factors, and the transcript sizes are described in more detail
below.
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), whereas no staining
could be seen in the primordial follicles. GATA-4 antigen was evident
also in granulosa cells of preantral follicles (Fig. 2B), but the
strongest immunoreactivity was observed in granulosa cells of large
antral follicles where both cumulus and mural granulosa cells showed
uniform staining for GATA-4 (Fig. 2C). Lesser staining was found in
thecal cells and in stromal cells between the follicles. No staining
could be detected in oocytes (Fig. 2C) or in corpus luteum (data not
shown). The immunohistochemical localization of GATA-4 protein, thus,
coincides with that of GATA-4 mRNA as detected by in situ
hybridization. No immunoreactivity was detected when sections were
incubated with nonimmune IgG as the primary antibody (data not shown).
We did not have antibodies suitable for immunohistochemistry of GATA-6
and FOG-2 at our disposal.
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To study whether ovarian sex cord-derived tumors
(i.e. granulosa cell tumors and thecomas) express GATA-4,
GATA-6, and FOG-2 transcripts, tumor specimens were subjected to
Northern hybridization with probes for these factors. GATA-4 mRNA
expression was detected in all 15 granulosa cell tumors and in 8 of 9
theca cell tumors; GATA-6 transcripts were expressed in 9 of 10
granulosa cell tumor samples and in all of the 4 thecomas studied.
FOG-2 mRNA was detected in all of the 12 granulosa cell tumors and 7
theca cell tumors studied. Examples of GATA-4, GATA-6, and FOG-2 mRNA
expression in sex cord tumors are shown in Fig. 2
, A and B. Neither
GATA-4 nor GATA-6 was expressed in specimens of serous or mesonephroid
ovarian cancer (Fig. 3A), which are
derivatives of the ovarian surface epithelium. To study the
localization of GATA-4 protein in sex cord-derived tumors,
immunohistochemical analysis was carried out. Immunoreactivity for
GATA-4 was present in the tumor cells of both granulosa and theca cell
tumors (Fig. 3, C and D). By contrast, no staining could be detected in
endothelial cells lining a small blood vessel (Fig. 3C).
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We next studied whether freshly isolated human preovulatory
granulosa cells, obtained from women undergoing ovarian
hyperstimulation for in vitro fertilization, are able
to express GATA-4 and GATA-6 transcripts. We also studied expression of
these transcripts in cultured human GL cells. Using Northern blot
analysis, we detected 4.4-kb and 3.8-kb transcripts for GATA-4 and
GATA-6 (42, 43), respectively, in both freshly isolated
preovulatory granulosa cells (Fig. 4, A
and B, lanes 1 and 2) as well as in GL cells cultured for 6 days (Fig. 4, A and B, lane 3). Next, we examined whether FOG-2 transcripts are
expressed in human GL cells. Using RT-PCR, we amplified a 342-bp FOG-2
fragment from human preovulatory granulosa cell RNA (Fig. 4C). Northern
blot analysis further showed that an approximately 4.5-kb transcript
can be detected in freshly isolated granulosa cells, corresponding to
the transcript size reported by Holmes et al.
(31) (Fig. 4D, lanes 1 and 2). As with GATA-4 and -6 (Fig. 4, A and B, lane 3), the expression level of FOG-2, as corrected to
cyclophilin, remained stable when the cells were maintained in the
culture (Fig. 4D, lane 3).
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Because gonadotropins have been shown to regulate the expression
of GATA-4 and GATA-6 mRNA in mouse ovaries (19), Northern
and dot blot hybridization with specific probes was carried out to
determine if rhFSH, hCG or 8-Br-cAMP would affect the expression of
GATA-4, GATA-6, or FOG-2 mRNA in cultured GL cells. No changes in
GATA-4 or FOG-2 steady-state mRNA levels were observed with any of
hormone treatments tested (data not shown). In contrast, treatment of
the cells with hCG resulted in a modest albeit statistically
significant increase in steady-state levels of GATA-6 mRNA. Figure 5A shows that an 8-h treatment with 30
ng/mL hCG raised GATA-6 transcript levels on days 3 and 5 of culture.
In the same experiment hCG stimulation increased inhibin- mRNA
levels approximately 1.3 and 2 times vs. control cultures
(days 3 and 5, respectively; data not shown). Time-dependence studies
performed on day 7 of culture showed that although GATA-6 mRNA levels
were induced as early as 2 h after hCG treatment, the effect was
statistically significant (P < 0.05) only at the 6-h
time point (Fig. 5B). Because hCG increases intracellular cAMP levels
in human GL cells, we tested whether a cell permeable cAMP analog,
8-Br-cAMP, could also increase GATA-6 mRNA levels in these cells.
Figure 5C shows an experiment in which stimulation with 0.5 mmol/L
8-Br-cAMP moderately increased GATA-6 mRNA levels in GL cells within 2
h of stimulation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In both mouse and human granulosa cells, GATA-4 expression correlates with active cell proliferation. GATA-4 mRNA levels decrease abruptly in mouse granulosa cells before follicular atresia through programmed cell death (19), implying that this transcription factor may participate in the regulation of the antiapoptotic pathway within the ovary. Thus, we speculate that continued expression of GATA-4 in granulosa and theca cell tumors may promote growth by limiting apoptosis. Supporting this contention, enhanced or persistent expression of GATA-4 has been associated with other tumors, including adrenocortical carcinomas (22), and endodermal sinus tumor (44), and esophageal/gastric adenocarcinomas (45). Of interest, down-regulation of GATA-1 and GATA-2 is associated with increased apoptosis in hematopoietic and other nonovarian cell types (46, 47, 48, 49) suggesting a more general role for this protein family in the regulation of apoptosis.
Relatively little is known about the target genes regulated by GATA-4,
GATA-6, and FOG-2 in normal ovarian tissue or sex cord-derived tumors.
GATA-4 has been implicated in the regulation of certain genes expressed
by gonadal somatic cells, including AMH (20, 23, 24),
inhibin- (21), and steroidogenic acute regulatory
protein (50). In Sertoli cells, GATA-4 seems to work
synergistically with SF-1 in the regulation of the AMH promoter
(23). Consistent with our finding of GATA-4 expression in
human tumor specimens, the putative target genes AMH and inhibin-
have been shown to be expressed in sex cord-derived tumors
(51). On the basis of its pattern of expression, GATA-6
may be critical for maintenance of the corpus luteum (19),
although the specific genes regulated by GATA-6 in luteal or granulosa
cells are not known.
The factors regulating the expression/activity of GATA-binding proteins in normal ovarian tissue are not well characterized. Stimulation of mouse gonadal cell lines with forskolin, which mimics gonadotropin stimulation, causes a 70% increase in steady-state GATA-6 mRNA (19). Similarly, treatment of human GL cell cultures with 8-Br-cAMP results in a modest increase in GATA-6 mRNA expression. In mouse granulosa cell lines, stimulation with hCG or FSH increases GATA-4 mRNA by 20–50% (19). On the other hand, hCG does not alter GATA-4 mRNA levels in cultured human GL cells. This lack of an hCG effect may reflect inherent differences in these cell types. Although some degree of contamination of cultured human granulosa cells with other cell types is possible (52), major number of the cells in this culture model is derived from preovulatory follicles and luteinize during in vitro culture (32). Functionally, these cells resemble the early corpus luteum, and, therefore, the effects on GATA-6 rather than GATA-4 are not unexpected given that luteal cells express GATA-6 more readily than GATA-4 also in vivo (19).
Taken together, these studies indicate that GATA-4, GATA-6, and FOG-2 are expressed in human ovary and cultured ovarian somatic cells. Moreover, the abundant expression of these factors in the human sex cord-derived tumors suggests that they may play a role in the growth and differentiation of ovarian stromal cells. Additional studies are needed to identify the target genes and interacting proteins of the GATA factors in human ovaries.
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Acknowledgments |
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Footnotes |
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2 These authors contributed equally to this work.
Received January 8, 2000.
Revised May 15, 2000.
Accepted June 7, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-myosin heavy-chain-encoding gene and
isolation of a human GATA-4 cDNA. Gene. 155:219–223.[CrossRef][Medline]
- inhibin, and CD99
expression in sex cord-stromal tumors and endometrioid ovarian
carcinomas resembling sex cord-stromal tumors. Hum Pathol. 29:840–845.[CrossRef][Medline]
: implications of white blood
cells in culture. Obstet Gynecol. 84:121–127.[Medline]
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 C. D. Capo-chichi, I. H. Roland, L. Vanderveer, R. Bao, T. Yamagata, H. Hirai, C. Cohen, T. C. Hamilton, A. K. Godwin, and X.-X. Xu Anomalous Expression of Epithelial Differentiation-determining GATA Factors in Ovarian Tumorigenesis Cancer Res., August 15, 2003; 63(16): 4967 - 4977. [Abstract] [Full Text] [PDF]
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J. R. Wood, V. L. Nelson, C. Ho, E. Jansen, C. Y. Wang, M. Urbanek, J. M. McAllister, S. Mosselman, and J. F. Strauss III The Molecular Phenotype of Polycystic Ovary Syndrome (PCOS) Theca Cells and New Candidate PCOS Genes Defined by Microarray Analysis J. Biol. Chem., July 11, 2003; 278(29): 26380 - 26390. [Abstract] [Full Text] [PDF]
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I. Ketola, J. Toppari, T. Vaskivuo, R. Herva, J. S. Tapanainen, and M. Heikinheimo Transcription Factor GATA-6, Cell Proliferation, Apoptosis, and Apoptosis-Related Proteins Bcl-2 and Bax in Human Fetal Testis J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1858 - 1865. [Abstract] [Full Text] [PDF]
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 M. Anttonen, I. Ketola, H. Parviainen, A.-K. Pusa, and M. Heikinheimo FOG-2 and GATA-4 Are Coexpressed in the Mouse Ovary and Can Modulate Mullerian-Inhibiting Substance Expression Biol Reprod, April 1, 2003; 68(4): 1333 - 1340. [Abstract] [Full Text] [PDF]
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C. Gillio-Meina, Y. Y. Hui, and H. A. LaVoie GATA-4 and GATA-6 Transcription Factors: Expression, Immunohistochemical Localization, and Possible Function in the Porcine Ovary Biol Reprod, February 1, 2003; 68(2): 412 - 422. [Abstract] [Full Text] [PDF]
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J. J. Tremblay, F. Hamel, and R. S. Viger Protein Kinase A-Dependent Cooperation between GATA and CCAAT/Enhancer-Binding Protein Transcription Factors Regulates Steroidogenic Acute Regulatory Protein Promoter Activity Endocrinology, October 1, 2002; 143(10): 3935 - 3945. [Abstract] [Full Text] [PDF]
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N. M. Robert, J. J. Tremblay, and R. S. Viger Friend of GATA (FOG)-1 and FOG-2 Differentially Repress the GATA-Dependent Activity of Multiple Gonadal Promoters Endocrinology, October 1, 2002; 143(10): 3963 - 3973. [Abstract] [Full Text] [PDF]
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S. Kiiveri, J. Liu, M. Westerholm-Ormio, N. Narita, D. B. Wilson, R. Voutilainen, and M. Heikinheimo Differential Expression of GATA-4 and GATA-6 in Fetal and Adult Mouse and Human Adrenal Tissue Endocrinology, August 1, 2002; 143(8): 3136 - 3143. [Abstract] [Full Text] [PDF]
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C. K. Cheng, C. M. Yeung, B. K. C. Chow, and P. C. K. Leung Characterization of a New Upstream GnRH Receptor Promoter in Human Ovarian Granulosa-Luteal Cells Mol. Endocrinol., July 1, 2002; 16(7): 1552 - 1564. [Abstract] [Full Text] [PDF]
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T. E. Vaskivuo, M. Anttonen, R. Herva, H. Billig, M. Dorland, E. R. te Velde, F. Stenback, M. Heikinheimo, and J. S. Tapanainen Survival of Human Ovarian Follicles from Fetal to Adult Life: Apoptosis, Apoptosis-Related Proteins, and Transcription Factor GATA-4 J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3421 - 3429. [Abstract] [Full Text] [PDF]
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D. B. Hales Editorial: Gonadal-Specific Transcription Factors--GATA (Go) 4 It! Endocrinology, March 1, 2001; 142(3): 974 - 976. [Full Text] [PDF]
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J. J. Tremblay and R. S. Viger GATA Factors Differentially Activate Multiple Gonadal Promoters through Conserved GATA Regulatory Elements Endocrinology, March 1, 2001; 142(3): 977 - 986. [Abstract] [Full Text] [PDF]
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I. Ketola, V. Pentikäinen, T. Vaskivuo, V. Ilvesmäki, R. Herva, L. Dunkel, J. S. Tapanainen, J. Toppari, and M. Heikinheimo Expression of Transcription Factor GATA-4 during Human Testicular Development and Disease J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3925 - 3931. [Abstract] [Full Text]
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