Human fetal membranes play an important role in term and preterm labor and are responsive to steroids. We examined the expression of steroid receptor coactivators in fetal membranes obtained prior to and following labor at term. Proteins were localized by immunohistochemistry, Western analysis was carried out in nuclear extracts, and mRNA levels were determined by real-time RT-PCR. SRC-1, SRC-2, p300, and PCAF proteins were present in all nuclear extracts. The amnion nuclei expressed higher levels of SRC-1, p300, and PCAF than nuclei from the chorion-decidua, whereas the reverse was true for SRC-2. Chorion-decidua from patients before labor expressed higher levels of SRC-1 than those from patients after labor. Also, the PCAF level was higher in the amnion obtained before labor than the same tissue obtained after labor. In contrast to the protein expression, mRNA levels of SRC-1 and p300 were higher in the chorion-decidua compared to the amnion, whereas there was no difference in levels of SRC-2 and PCAF mRNAs between these two tissues. These data underline that the regulation of the expression of the coactivators in these tissues occurs during labor and is complex and tissue specific. 1. Introduction Preterm birth remains the leading cause of perinatal mortality and morbidity. Despite intensive efforts towards prevention, prompt diagnosis, and use of a variety of tocolytics, the incidence of preterm birth has increased [1]. This is in part due to lack of understanding of the mechanisms responsible for the initiation of labor. Understanding the molecular basis for labor is essential for the prevention, early diagnosis, and effective treatment of preterm labor. The onset of labor in pregnant women involves multiple complex pathways including both endocrine and mechanical signals [2, 3]. In both the human and sheep, glucocorticoids and progesterone appear to play a central role in the parturition. In the fetal membranes, glucocorticoids increase the expression of type 2 prostaglandin H2 synthase (PGHS-2), a rate-limiting enzyme for the production of prostaglandins (PGs), in the amnion cells in culture [4, 5]. Glucocorticoids also inhibit the expression and activity of 15-hydroxyprostaglandin dehydrogenase (PGDH), the major PG degrading enzyme, in the human fetal membranes, and progesterone is believed to tonically stimulate expression of this enzyme [6]. Furthermore, glucocorticoids stimulate the expression of corticotropin-releasing hormone (CRH) in the fetal membranes and placenta [7, 8], and CRH has also been shown to stimulate PG production [9]. These
References
[1]
R. L. Goldenberg and D. J. Rouse, “Prevention of premature birth,” The New England Journal of Medicine, vol. 339, no. 5, pp. 313–320, 1998.
[2]
J. R. G. Challis, S. G. Matthews, W. Gibb, and S. J. Lye, “Endocrine and paracrine regulation of birth at term and preterm,” Endocrine Reviews, vol. 21, no. 5, pp. 514–550, 2000.
[3]
S. J. Lye, J. Mitchell, N. Nashman et al., “Role of mechanical signals in the onset of term and preterm labor,” Frontiers of Hormone Research, vol. 27, pp. 165–178, 2001.
[4]
T. Zakar, J. J. Hirst, J. E. Mijovic, and D. M. Olson, “Glucocorticoids stimulate the expression of prostaglandin endoperoxide H synthase-2 in amnion cells,” Endocrinology, vol. 136, no. 4, pp. 1610–1619, 1995.
[5]
P. Economopoulos, M. Sun, B. Purgina, and W. Gibb, “Glucocorticoids stimulate prostaglandin H synthase type 2 (PGHS-2) in the fibroblast cells in human amnion culture,” Molecular and Cellular Endocrinology, vol. 117, no. 2, pp. 141–147, 1996.
[6]
F. A. Patel, V. L. Clifton, K. Chwalisz, and J. R. G. Challis, “Steroid regulation of prostaglandin dehydrogenase activity and expression in human term placenta and chorio-decidua in relation to labor,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 1, pp. 291–299, 1999.
[7]
D. M. Frim, R. L. Emanuel, B. G. Robinson, C. M. Smas, G. K. Adler, and J. A. Majzoub, “Characterization and gestational regulation of corticotropin-releasing hormone messenger RNA in human placenta,” Journal of Clinical Investigation, vol. 82, no. 1, pp. 287–292, 1988.
[8]
S. A. Jones, A. N. Brooks, and J. R. G. Challis, “Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta,” Journal of Clinical Endocrinology and Metabolism, vol. 68, no. 4, pp. 825–830, 1989.
[9]
M. McLean and R. Smith, “Corticotrophin-releasing hormone and human parturition,” Journal of the Society for Gynecologic Investigation, vol. 8, pp. 122–133, 2001.
[10]
W. Gibb, “The role of prostaglandins in human parturition,” Annals of Medicine, vol. 30, no. 3, pp. 235–241, 1998.
[11]
F. A. Potestio, T. Zakar, and D. M. Olson, “Glucocorticoids stimulate prostaglandin synthesis in human amnion cells by a receptor-mediated mechanism,” Journal of Clinical Endocrinology and Metabolism, vol. 67, no. 6, pp. 1205–1210, 1988.
[12]
K. Karalis, G. Goodwin, and J. A. Majzoub, “Cortisol blockade of progesterone: a possible molecular mechanism involved in the initiation of human labor,” Nature Medicine, vol. 2, no. 5, pp. 556–560, 1996.
[13]
M. J. Tsai and B. W. O'Malley, “Molecular mechanisms of action of steroid/thyroid receptor superfamily members,” Annual Review of Biochemistry, vol. 63, pp. 451–486, 1994.
[14]
N. J. McKenna and B. W. O'Malley, “Combinatorial control of gene expression by nuclear receptors and coregulators,” Cell, vol. 108, no. 4, pp. 465–474, 2002.
[15]
N. J. McKenna and B. W. O’Malley, “Minireview: nuclear receptor coactivators—an update,” Endocrinology, vol. 143, pp. 2461–2465, 2002.
[16]
C. Leo and J. D. Chen, “The SRC family of nuclear receptor coactivators,” Gene, vol. 245, no. 1, pp. 1–11, 2000.
[17]
K. C. Lee and W. L. Kraus, “Nuclear receptors, coactivators and chromatin: new approaches, new insights,” Trends in Endocrinology and Metabolism, vol. 12, no. 5, pp. 191–197, 2001.
[18]
B. J. Deroo and T. K. Archer, “Glucocorticoid receptor-mediated chromatin remodeling in vivo,” Oncogene, vol. 20, no. 24, pp. 3039–3046, 2001.
[19]
M. Sun, M. Ramirez, J. R. G. Challis, and W. Gibb, “Immunohistochemical localization of the glucocorticoid receptor in human fetal membranes and decidua at term and preterm delivery,” Journal of Endocrinology, vol. 149, no. 2, pp. 243–248, 1996.
[20]
J. C. Condon, P. Jeyasuria, J. M. Faust, J. W. Wilson, and C. R. Mendelson, “A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 16, pp. 9518–9523, 2003.
[21]
X. Dong, O. Shylnova, J. R. G. Challis, and S. J. Lye, “Identification and characterization of the protein-associated splicing factor as a negative co-regulator of the progesterone receptor,” Journal of Biological Chemistry, vol. 280, no. 14, pp. 13329–13340, 2005.
[22]
Q. Li, A. Su, J. Chen, Y. A. Lefebvre, and R. J. G. Haché, “Attenuation of glucocorticoid signaling through targeted degradation of p300 via the 26S proteasome pathway,” Molecular Endocrinology, vol. 16, no. 12, pp. 2819–2827, 2002.
[23]
M. Sun, J. Kingdom, D. Baczyk, S. J. Lye, S. G. Matthews, and W. Gibb, “Expression of the multidrug resistance P-glycoprotein, (ABCB1 glycoprotein) in the human placenta decreases with advancing gestation,” Placenta, vol. 27, no. 6-7, pp. 602–609, 2006.
[24]
D. Yeboah, G. M. Kalabis, M. Sun, R. C. Ou, S. G. Matthews, and W. Gibb, “Expression and localisation of breast cancer resistance protein (BCRP) in human fetal membranes and decidua and the influence of labour at term,” Reproduction, Fertility and Development, vol. 20, no. 2, pp. 328–334, 2008.
[25]
M. Lappas, T. L. Odumetse, C. Riley et al., “Pre-labour fetal membranes overlying the cervix display alterations in inflammation and NF-κB signalling pathways,” Placenta, vol. 29, no. 12, pp. 995–1002, 2008.
[26]
J. Xu and Q. Li, “Review of the in Vivo functions of the p160 steroid receptor coactivator family,” Molecular Endocrinology, vol. 17, no. 9, pp. 1681–1692, 2003.
[27]
I. Kurihara, H. Shibata, T. Suzuki et al., “Expression and regulation of nuclear receptor coactivators in glucocorticoid action,” Molecular and Cellular Endocrinology, vol. 189, no. 1-2, pp. 181–189, 2002.
[28]
J. Zhao, A.-Y. Gong, R. Zhou, J. Liu, A. N. Eischeid, and X.-M Chen, “Downregulation of PCAF by miR-181a/b provides feedback regulation to TNF-α- induced transcription of proinflammatory genes in liver epithelial cells,” The Journal of Immunology, vol. 188, pp. 1266–1274, 2012.
[29]
J. Chen and Q. Li, “Life and death of transcriptional co-activator p300,” Epigenetics, vol. 6, no. 8, pp. 957–961, 2011.
[30]
C. W. R. Ou, M. Sun, W. Sadej, and W. Gibb, “Glucocorticoid and progesterone receptors, and nuclear receptor coactivators in the human fetal membranes,” in Proceedings of the 52nd Annual Meeting of the Society for Gynecologic Investigation, p. 135, Los Angeles, Calif, USA, 2005.
[31]
S. Goldman, A. Weiss, I. Almalah, and E. Shalev, “Progesterone receptor expression in human decidua and fetal membranes before and after contractions: possible mechanism for functional progesterone withdrawal,” Molecular Human Reproduction, vol. 11, no. 4, pp. 269–277, 2005.
[32]
G. J. Haluska, T. R. Wells, J. J. Hirst, R. M. Brenner, D. W. Sadowsky, and M. J. Novy, “Progesterone receptor localization and isoforms in myometrium, decidua, and fetal membranes from rhesus macaques: evidence for functional progesterone withdrawal at parturition,” Journal of the Society for Gynecologic Investigation, vol. 9, no. 3, pp. 125–136, 2002.
