| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Regular Article |
a Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, and the Departments of Obstetrics & Gynaecology and of Physiology, University of Toronto, Toronto, Ontario, Canada M5G 1X5
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
gene regulation, parturition, progesterone, uterus
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
During late pregnancy, there are important structural changes in the uterus, including extracellular matrix deposition, cellular remodeling, and myometrial cell growth (reviewed in [6]). Interestingly, laminin, collagen, elastin, and fibronectin, which make up the basement membrane, contain AP-1 sites in their promoter regions and may therefore be regulated by AP-1 proteins [7–10]. In addition, extracellular matrix remodeling enzymes, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), contain AP-1 sites within their promoter regions (reviewed in [11–13]). Prior to the onset of labor, the myometrium changes from a quiescent state to a highly excitable state that is capable of producing strong coordinated contractions. These changes in contractile capability are brought about by an increase in the expression of a cassette of genes, termed contraction-associated proteins (CAPs), which include the gap junction connexin 43 (Cx43), the oxytocin receptor (OTR) and the prostaglandin F2
receptor (FP; reviewed in [14]). Both the Cx43 and OTR promoters contain consensus AP-1 sites, which mediate responsiveness to the phorbol ester TPA (12-O-tetradecanoylphorbol-13-acetate) in myometrial cells and MCF7 cells, respectively, while the rat FP promoter does not contain any consensus AP-1 sites [15–17]. Since the promoter regions of many structural and remodeling genes as well as specific CAP genes contain AP-1 sites, it is possible that AP-1 transcription factors are involved in modulating the expression of genes involved in both uterine remodeling during pregnancy and the onset of labor.
Previous studies in both pregnant and nonpregnant rats have suggested a correlation between the induction of AP-1 and CAP genes. In nonpregnant myometrium, estrogen treatment has been shown to induce the expression of c-fos, c-jun, junD, and junB [18, 19]. In similar studies, the levels of Cx43, OTR, and FP mRNA were increased by estrogen treatment of nonpregnant animals [20–22]. This induction of Cx43 was preceded by the induction of c-fos mRNA and was inhibited by cyclohexamide, indicating the requirement for de novo protein synthesis and potentially c-Fos protein [5]. In pregnant animals, the increase in CAP gene expression has been correlated with an increase in the maternal estrogen:progesterone ratio (reviewed in [14]). Furthermore, the induction of c-fos, Cx43, OTR, and FP mRNA is inhibited by progesterone treatment, which also delays the onset of labor [5, 23, 24]. In addition to hormonal signals, c-fos and c-jun mRNA levels have been shown to increase in response to mechanical stretch in smooth muscle cells (reviewed in [25]). In unilaterally pregnant rats, mechanical stretch of the empty horn, by insertion of a tube, caused a dramatic increase in the expression of Cx43 and OTR, while the levels of FP were unaffected [23, 24, 26]. Thus, AP-1 proteins may be capable of transducing both the hormonal and mechanical signals involved in the expression of CAP genes, which contain AP-1 sites in their promoter regions.
Our previous data have suggested a role for c-Jun and c-Fos during pregnancy in the induction of Cx43 and the onset of labor [5]. However, since other AP-1 proteins have been shown to respond to estrogen treatment in non-pregnant myometrium, we hypothesize that several AP-1 family members have a role in the onset of labor both in the regulation of CAP genes which contain AP-1 sites in their promoter regions and genes required for myometrial remodeling. These transcription factors may serve as master control genes in the preparation of the myometrium for the process of labor. In this study we used a rat model to investigate myometrial mRNA levels of AP-1 transcription factors during normal, progesterone delayed and RU486-induced preterm labor. In addition, we investigated the effect of gravidity on the expression of AP-1 transcription factors using a unilateral tubal-ligation model.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Female virgin Wistar rats (Charles River Co., St. Constant, PQ, Canada) were mated with male Wistar rats. Day 1 of gestation was designated as the day a vaginal plug was observed. Female rats were then housed individually under standard environmental conditions (12L:12D cycle) and given Purina Rat Chow (Ralston Purina, St. Louis, MO) and water ad libitum. Under these conditions, the time of delivery was during the morning of Day 23. Animals were designated as being in labor when at least 1 pup was delivered. All animal experiments were approved by the institutional animal care committee.
Gestational profile In order to determine the temporal changes in the mRNA levels of the AP-1 gene family members throughout gestation, myometrial samples were collected from pregnant rats on Gestational Days 12, 15, 17, 19, 21, 22, and 23 or 1 day postpartum (1PP). Tissue was collected at 1000 h on all days with the following exceptions: on Day 22, an additional sample (d22pm) was collected at 2300 h; on Day 23, a "not in labor" (d23NIL) sample was collected at 0600 h; while the labor (d23L) sample was collected once the animals had delivered at least 1 pup (n = 3).
Progesterone-delayed labor In order to observe the effect of delaying labor by maintaining high levels of progesterone, pregnant rats were randomly assigned daily s.c. (1000 h) treatments of either progesterone (16 mg/kg in 0.2 ml corn oil containing 10% ethyl alcohol; Sigma, St. Louis, MO) or vehicle starting on Day 20 of gestation. Myometrial samples were collected on Day 21, 22, or 23 during labor in the vehicle-treated group or Day 21, 22, 23, or 24 in the progesterone-treated group (n = 3).
RU486-induced preterm labor Pregnant rats were randomly assigned for treatment on Day 19 with either RU486 (10 mg/kg s.c. at 1000 h in 0.5 ml corn oil containing 10% ethyl alcohol, mifepristone; 17ß-hydroxy-11ß-[4-dimethylaminophenyl'-17-[1-propynyl'-estra-4,10-dien-3-1; Sigma) or vehicle. Myometrial samples were collected from both groups of animals on Day 20 when the RU486 treated animals had delivered at least 1 pup (n = 4).
Unilaterally pregnant rats Virgin female rats were subjected to unilateral tubal ligation as described in Ou et al. [23]. Animals were allowed to recover from surgery for at least 5 days before mating. After mating, myometrial samples were collected on Days 15, 17, 19, 21, 22, 23, or 1PP (n = 3). At the time of tissue collection, the ligated empty horn was separated from the gravid horn.
Tissue Collection
Animals were killed by asphyxiation in carbon dioxide gas. Uterine horns were removed, bisected longitudinally, dissected away from both pups and placentas, and placed in ice-cold phosphate-buffered saline (PBS). The endometrium was separated from the myometrial tissue by mechanical scraping on ice, which we have previously shown removes the entire luminal epithelium and the majority of the uterine stroma [5]. The tissue was then flash frozen in liquid nitrogen and stored at -70°C.
Complementary DNA Probes
The cDNA probes were obtained from the ATCC (American Type Culture Collection) for c-jun (63026), junD (95654), and fosB (63118). The following probes were provided by other research labs: rat c-fos cDNA (Dr. Curran, Roche Research Center, Nutley, NJ), mouse junB (Dr. Woodgett, Ontario Cancer Institute, Toronto, ON, Canada), and 18s ribosomal protein (Dr. Denhardt, Rutgers University, Piscataway, NJ). Probes for rat fra-1 (GenBank M19651) and fra-2 (GenBank U18913) were generated by PCR using the following primers: fra-1 upper, 5'-CCAGCAAGCGCAGACACAGAC-3'; fra-1 lower, 5'-CGGAGGAGGGGTCACCACTG-3'; fra-2 upper, 5'-ATCCCGGGAACTTTGACACCT-3'; fra-2 lower, 5'-GGCTCTTCCCCGTAGAAACCA-3'.
Northern Analysis
Frozen tissue was crushed under liquid nitrogen using a mortar and pestle. Crushed tissue was homogenized for 1 min in Trizol (Gibco BRL, Grand Island, NY), and RNA was extracted according to the manufacturer's specifications. Purified RNA (10 µg) was then analyzed by Northern analysis. RNA was separated on 1% (wt:vol) agarose (Gibco BRL) gel containing 3.7% (vol:vol) formaldehyde (J.T. Baker, Phillipsburg, NJ) in MOPS (3-[N-morpholino]propanesulfonic acid; Sigma), transferred in 0.1 M sodium phosphate (NaP; Sigma) onto a nylon membrane (GeneScreen; DuPont, NEN Research Products, Boston, MA), and cross-linked by ultraviolet irradiation. The cDNA probes were labeled with [-32P]dCTP (NEN Research Products) using the multiprime DNA labeling system. Hybridization was conducted at 55°C in 30% formamide for 20 h according to the method described in Bio-Rad bulletin 1110 (Bio-Rad Laboratories, Richmond, CA). Subsequently, the membrane was washed to a final stringency of 30 mM NaP/0.1% SDS (EM Science, Darmstadt, Germany). All RNA isolation and analysis was carried out in DEPC (diethyl pyrocarbonate; Sigma) water. Probed membranes were exposed to x-ray film (Kodak XAR; Eastman Kodak, Rochester, NY) with an intensifying screen at -70°C and were analyzed by densitometry.
Statistical Analysis
Gestational profiles were subjected to a one-way ANOVA followed by pairwise multiple comparison procedures (Student-Newman-Keuls method) to determine differences between groups. Progesterone (Days 21, 22, and 23) and tubal-ligation data were analyzed by two-way ANOVA followed by pairwise multiple comparison procedures as described above. The Day 24 progesterone-treated group was compared with the Day 23 vehicle group using a t-test. RU486 results were compared with vehicle using a t-test. Where required, the data were transformed by the appropriate method to obtain a normal distribution. Statistical analysis was carried out using SigmaStat version 1.01 (Jandel Corp., San Rafael, CA) with the level of significance for comparison set at P < 0.05.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Gestational Analysis
Myometrial tissue was collected on Gestational Days 12, 15, 17, 19, 21, 22 (morning and night), 23NIL (not in labor), 23L (in labor), and 1 day postpartum (1PP) for Northern analysis of fos and jun transcripts. Myometrial levels of c-fos, fosB, and fra-1 mRNA remained low throughout most of gestation but showed a dramatic increase during labor on Day 23 and a subsequent reduction on 1PP (Fig. 1). Densitometric analysis revealed that this 8- to 10-fold increase was statistically different from all other gestational days (P < 0.001). The levels of fra-2 mRNA began to increase during late gestation, with a significant difference detected on Day 21 (P < 0.05), a further increase detected on Day 23L (P < 0.001), and a decrease in mRNA levels on 1PP.
|
Northern analysis revealed myometrial levels of c-jun and junD mRNA remained relatively constant throughout gestation while the levels of junB mRNA increased dramatically on Day 23 and returned to low levels by 1PP (Fig. 2). Densitometric analysis revealed that the 4-fold increase in junB mRNA observed on Day 23 during labor was significantly different from the levels on all other gestational days (P < 0.001). In contrast, the levels of c-jun mRNA remained relatively constant throughout gestation; there was, however, a small but significant increase detected on Day 23 during labor compared with the Day 12 levels but not compared with other gestational days (P < 0.05). Similarly, the levels of junD remained relatively constant throughout gestation, though with a significant reduction detected prior to the onset of labor (P < 0.05).
|
Progesterone-Delayed Labor
Pregnant rats were treated starting on Day 20 with daily injections of progesterone. This treatment prevents the onset of labor and has been shown to block the increase in myometrial CAP gene expression [5, 23, 24]. This treatment also prevented the increase in expression of c-fos, fosB, fra-1, and fra-2 mRNA (Fig. 3). Progesterone treatment caused dramatic reductions in the levels of c-fos and fra-1 on both Days 23 and 24 compared with the vehicle sample on Day 23, which was a laboring sample. The levels of fosB were significantly reduced on Day 23 compared with vehicle. The levels of fra-2, which begin to rise earlier in normal gestation, were inhibited by progesterone treatment on Days 22, 23, and 24. In contrast, the levels of junD (which do not change dramatically throughout gestation) were unaffected by progesterone treatment (Fig. 4). The levels of c-jun were slightly reduced by progesterone treatment on Days 23 and 24, while the levels of junB were dramatically and significantly reduced on Days 23 and 24 (P < 0.001).
|
|
RU486-Induced Preterm Labor
Treatment of pregnant rats with the progesterone receptor antagonist RU486 on Day 19 caused the onset of preterm labor within 24 h and has been shown to induce the expression of CAP genes [5, 23, 24]. Northern analysis revealed that c-fos, fra-1, and fra-2 mRNA levels were significantly induced by RU486 treatment (Fig. 5). In contrast, fosB mRNA expression showed a trend toward an increase but did not reach significance. RU486 treatment did not significantly affect the levels of c-jun mRNA, while the levels of junD were slightly increased (Fig. 6). In contrast, the levels of junB were dramatically increased by RU486 treatment and the onset of preterm labor (P < 0.001).
|
|
Unilaterally Pregnant Rats
We have previously shown that increased expression of the CAP genes Cx43 and OTR during labor occurs only in the gravid horn of unilaterally pregnant rats [23, 24, 26]. Based on other experiments, we have interpreted these data as demonstrating a role for stretch in inducing CAP gene expression. To determine whether AP-1 family members exhibit a similar regulation, we measured mRNA levels for these genes in empty and gravid horns of unilaterally pregnant rats. Northern analysis indicated a dramatic induction of c-fos, fosB, fra-1, and fra-2 in the gravid horn compared with the empty horn on Day 23 during labor (Fig. 7). Examination of jun family mRNA revealed no difference between the empty and gravid horns for c-jun and junD on all gestational days examined (Fig. 8). However, junB showed a dramatic induction in the gravid horn compared with the empty horn on Day 23L (Fig. 8).
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The gestational expression profiles for c-fos, fosB, and fra-1 were similar, with significantly higher mRNA levels detected only during labor. This dramatic increase in the myometrial expression of fos family genes during labor likely leads to greater activation of AP-1 containing genes because Fos/Jun heterodimers are more potent activators of AP-1 sites than Jun/Jun dimers [3, 27]. These transcription factors may therefore increase the expression of other genes that are required specifically at the time of labor, including the CAP genes Cx43 and OTR. While the present data demonstrate a correlation between the expression of AP-1 genes and the CAP genes Cx43 and OTR during labor, other evidence suggests these transcription factors are capable of regulating the expression of these genes in the myometrium. In nonpregnant studies, estrogen treatment caused a dramatic increase in the expression of Cx43, which was preceded by a peak in c-fos mRNA and was dependent on de novo protein synthesis [5]. Furthermore, cotransfection of c-Fos and c-Jun expression vectors into myometrial cells caused an increase in Cx43 promoter activity, which was dependent on the AP-1 site [28].
In contrast, this study showed that fra-2 levels rose earlier on Day 21 and peaked during labor. This suggests a different role for the FRA-2 protein compared with other members of the Fos family. FRA-2 may increase the transcription of genes required in the preparation of the myometrium for labor. These include matrix and cellular remodeling genes, such as MMPs, TIMPs, and components of the basement membrane, all of which contain AP-1 binding sites in their promoter regions.
The mRNA levels of c-jun and junD remained relatively constant, while the mRNA levels of junB were dramatically increased during gestation. Although expression of c-jun and junD mRNA did not rise dramatically during labor, the presence of Jun proteins in the myometrium at the time of labor is likely important because Fos proteins are unable to form a functional dimer in the absence of a Jun family protein. Although Jun proteins are capable of forming functional homodimers, these are generally less activating than a Fos/Jun heterodimer and thus may not influence the expression of genes required for the onset of labor. The levels of junB increased significantly during labor, showing a similar profile to the Fos family. JunB, in contrast with other AP-1 proteins, is generally involved with antagonizing AP-1 sites and has been shown to inactivate both the c-jun and collagenase promoters, which contain AP-1 sites [29]. Furthermore, JunB has been shown to inhibit activation of AP-1 sites by c-Jun [29]. In the uterus, maximal induction of junB mRNA by estrogen was observed to mark a drop in the levels of the other jun family genes [19]. The presence of the inactivating JunB may contribute to the lack of a dramatic increase in the expression of other jun genes during labor.
Progesterone is the major hormone involved in the maintenance of pregnancy in the rat. Treatment of pregnant rats with progesterone prevents the onset of labor, while treatment with the progesterone receptor antagonist RU486 causes the onset of preterm labor. Here we have shown that many AP-1 family members are regulated by progesterone in the pregnant rat myometrium. The levels of c-fos, fra-1, fra-2, and junB were dramatically reduced by progesterone treatment and increased with RU486 treatment. Levels of fosB and c-jun were also reduced by progesterone, although less dramatically, while the levels of junD were unaffected. Similar regulation by progesterone during pregnancy has been observed for both Cx43 and OTR mRNA [5, 23]. These data provide further indirect evidence to support the modulation of Cx43 and OTR gene expression by AP-1 proteins.
In addition to hormonal regulation, mechanical stretch of the uterus imposed by the growing fetus has been shown to induce the expression of genes involved in the onset of labor. Increased expression of c-fos, fosB, fra-1, fra-2, and junB during labor only occurred in the gravid horn and not in the empty horn of unilaterally pregnant rats. This raises the intriguing possibility that AP-1 transcription factors may integrate the transduction of endocrine and mechanical signals during labor. The promoter region of the Cx43 and OTR genes contain conserved AP-1 sites. In the myometrium, Cx43 and OTR mRNA levels have been shown to increase in response to both mechanical and endocrine signals while FP mRNA was shown only to respond to endocrine signals in the pregnant myometrium [23, 24, 26]. The promoter region of the FP gene does not contain an AP-1 site, indicating that, while other factors, such as hormone receptors, may be involved in the hormonal responsiveness of several CAP genes, AP-1 proteins may be critical in the mechanical responsiveness of Cx43 and OTR during pregnancy.
In contrast with c-Fos and c-Jun, less is known about the cellular functions of the other AP-1 family members. Although all members of the AP-1 family can bind to the same consensus element, it has been shown that sequences flanking the AP-1 site influence the differential binding of various family members [4]. This may provide the ability for FRA-2/Jun complexes to act both at different gene promoters and earlier in gestation than the other members of the AP-1 family. Furthermore, AP-1 proteins have been shown to interact with other transcription factors including the CREB/ATF family, Maf proteins, and the estrogen and glucocorticoid receptors [30–33]. These interactions at specific promoters would provide a higher degree of specificity for AP-1 proteins in the regulation of gene expression, allowing for differential regulation of several genes by the same family of transcription factors. This study suggests that AP-1 transcription factors may serve as central regulatory proteins during late pregnancy capable of inducing genes required for both myometrial growth and remodeling during late pregnancy and the expression of specific CAP genes during labor.
|
FOOTNOTES |
|---|
1 This study was supported by a grant from the Canadian Institutes of Health Research (MOP 37775). J.A.M. is a recipient of a CIHR doctoral research award. 
2 Correspondence: Stephen J. Lye, Program in Development and Fetal Health, Samuel Lunenfeld Research Institute at Mount Sinai, 600 University Avenue, Suite 870, Toronto, ON, Canada M5G 1X5. FAX: 416 586 8740; lye{at}mshri.on.ca
Accepted: February 6, 2002.
Received: December 19, 2001.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  O. Shynlova, P. Tsui, A. Dorogin, and S. J. Lye Monocyte Chemoattractant Protein-1 (CCL-2) Integrates Mechanical and Endocrine Signals That Mediate Term and Preterm Labor J. Immunol., July 15, 2008; 181(2): 1470 - 1479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. O'Brien, J. J. Morrison, and T. J. Smith Upregulation of PSCDBP, TLR2, TWIST1, FLJ35382, EDNRB, and RGS12 Gene Expression in Human Myometrium at Labor Reproductive Sciences, April 1, 2008; 15(4): 382 - 393. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Dalrymple, K. Mahn, L. Poston, E. Songu-Mize, and R.M. Tribe Mechanical stretch regulates TRPC expression and calcium entry in human myometrial smooth muscle cells Mol. Hum. Reprod., March 1, 2007; 13(3): 171 - 179*. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ball, J. W. Wang, S. Wong, B. Zielnik, J. Mitchell, N. Wang, M. B. Stemerman, and B. F. Mitchell Phorbol ester treatment of human myometrial cells suppresses expression of oxytocin receptor through a mechanism that does not involve activator protein-1 Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E922 - E928. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Doring, O. Shynlova, P. Tsui, D. Eckardt, U. Janssen-Bienhold, F. Hofmann, S. Feil, R. Feil, S. J. Lye, and K. Willecke Ablation of connexin43 in uterine smooth muscle cells of the mouse causes delayed parturition J. Cell Sci., May 1, 2006; 119(9): 1715 - 1722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Sooranna, N. Engineer, J. A. Z. Loudon, V. Terzidou, P. R. Bennett, and M. R. Johnson The Mitogen-Activated Protein Kinase Dependent Expression of Prostaglandin H Synthase-2 and Interleukin-8 Messenger Ribonucleic Acid by Myometrial Cells: The Differential Effect of Stretch and Interleukin-1{beta} J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3517 - 3527. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.J. Williams, B.G. White, and D.J. MacPhee Expression of {alpha}5 Integrin (Itga5) Is Elevated in the Rat Myometrium During Late Pregnancy and Labor: Implications for Development of a Mechanical Syncytium Biol Reprod, May 1, 2005; 72(5): 1114 - 1124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Mitchell and S. J. Lye Differential Activation of the Connexin 43 Promoter by Dimers of Activator Protein-1 Transcription Factors in Myometrial Cells Endocrinology, April 1, 2005; 146(4): 2048 - 2054. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B G White, S J Williams, K Highmore, and D J MacPhee Small heat shock protein 27 (Hsp27) expression is highly induced in rat myometrium during late pregnancy and labour Reproduction, January 1, 2005; 129(1): 115 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Terzidou, S. R. Sooranna, L. U. Kim, S. Thornton, P. R. Bennett, and M. R. Johnson Mechanical Stretch Up-Regulates the Human Oxytocin Receptor in Primary Human Uterine Myocytes J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 237 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.A.Z. Loudon, S.R. Sooranna, P.R. Bennett, and M.R. Johnson Mechanical stretch of human uterine smooth muscle cells increases IL-8 mRNA expression and peptide synthesis Mol. Hum. Reprod., December 1, 2004; 10(12): 895 - 899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Mitchell, O. Shynlova, B. L. Langille, and S. J. Lye Mechanical stretch and progesterone differentially regulate activator protein-1 transcription factors in primary rat myometrial smooth muscle cells Am J Physiol Endocrinol Metab, September 1, 2004; 287(3): E439 - E445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Dogan, D. A. Deshpande, M. S. Kannan, and T. F. Walseth Changes in CD38 Expression and ADP-Ribosyl Cyclase Activity in Rat Myometrium During Pregnancy: Influence of Sex Steroid Hormones Biol Reprod, July 1, 2004; 71(1): 97 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Shynlova, J. A. Mitchell, A. Tsampalieros, B. L. Langille, and S. J. Lye Progesterone and Gravidity Differentially Regulate Expression of Extracellular Matrix Components in the Pregnant Rat Myometrium Biol Reprod, April 1, 2004; 70(4): 986 - 992. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.R. Sooranna, Y. Lee, L.U. Kim, A.R. Mohan, P.R. Bennett, and M.R. Johnson Mechanical stretch activates type 2 cyclooxygenase via activator protein-1 transcription factor in human myometrial cells Mol. Hum. Reprod., February 1, 2004; 10(2): 109 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Mitchell, T. C. Ting, S. Wong, B.F. Mitchell, and S. J. Lye Parathyroid Hormone-Related Protein Treatment of Pregnant Rats Delays the Increase in Connexin 43 and Oxytocin Receptor Expression in the Myometrium Biol Reprod, August 1, 2003; 69(2): 556 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Oltra, I. Pfeifer, and R. Werner Ini, a Small Nuclear Protein that Enhances the Response of the Connexin43 Gene to Estrogen Endocrinology, July 1, 2003; 144(7): 3148 - 3158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Oldenhof, O. P. Shynlova, M. Liu, B. L. Langille, and S. J. Lye Mitogen-activated protein kinases mediate stretch-induced c-fos mRNA expression in myometrial smooth muscle cells Am J Physiol Cell Physiol, November 1, 2002; 283(5): C1530 - C1539. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
