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Published in: BMC Pregnancy and Childbirth 1/2007

Open Access 01-06-2007 | Proceedings

Alternative splicing: an important mechanism for myometrial gene regulation that can be manipulated to target specific genes associated with preterm labour

Author: Alison Jane Tyson-Capper

Published in: BMC Pregnancy and Childbirth | Special Issue 1/2007

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Abstract

Considerable effort has been expended in attempting to distinguish genes that contribute to initiating the onset of term and preterm labour (PTL) from those that change in expression as a consequence of the progression of labour. The ability to define more clearly the genes involved in triggering labour contractions should lead to the development of new effective and safer strategies to prevent preterm birth. There is ample evidence to suggest that specific genes are co-ordinately regulated within the upper and lower regions of the myometrium prior to and during parturition and many of these genes are regulated by alternative pre-mRNA splicing. This mini-review highlights that expression of a range of different splicing factors, with defined roles in pre-mRNA splicing, is both temporally and spatially regulated within the uterine smooth muscle during pregnancy and labour. Moreover, several of these splicing factors play key roles in controlling the differential expression of specific regulatory proteins involved in uterine signalling and uterine quiescence. In addition, antisense morpholino oligonucleotide manipulation of pre-mRNA splicing may have potential in defining and targeting uterine pro-labour genes and thus contribute to the development of new therapeutic approaches to prevent PTL.
Literature
1.
go back to reference Nadal-Ginard B, Smith CW, Patton JG, Breitbart RE: Alternative splicing is an efficient mechanism for the generation of protein diversity: contractile protein genes as a model system. Adv Enzyme Regul. 1991, 31: 261-86. Review.CrossRefPubMed Nadal-Ginard B, Smith CW, Patton JG, Breitbart RE: Alternative splicing is an efficient mechanism for the generation of protein diversity: contractile protein genes as a model system. Adv Enzyme Regul. 1991, 31: 261-86. Review.CrossRefPubMed
2.
go back to reference Grammatopoulos DK, Dai Y, Randeva HS, Levine MA, Karteris E, Easton AJ, Hillhouse EW: A novel spliced variants of the type 1 corticoid-releasing hormone receptor with a deletion in the seventh transmembrane domain present in the human pregnant term myometrium and fetal membranes. Mol Endocrinol. 1999, 13: 2189-2202. 10.1210/me.13.12.2189.CrossRefPubMed Grammatopoulos DK, Dai Y, Randeva HS, Levine MA, Karteris E, Easton AJ, Hillhouse EW: A novel spliced variants of the type 1 corticoid-releasing hormone receptor with a deletion in the seventh transmembrane domain present in the human pregnant term myometrium and fetal membranes. Mol Endocrinol. 1999, 13: 2189-2202. 10.1210/me.13.12.2189.CrossRefPubMed
3.
go back to reference Havelock JC, Keller P, Muleba N, Mayhew BA, Casey BM, Rainey WE, Ann Word RA: Human Myometrial Gene Expression Before and During Parturition. Biol Reprod. 2005, 72: 707-719. 10.1095/biolreprod.104.032979.CrossRefPubMed Havelock JC, Keller P, Muleba N, Mayhew BA, Casey BM, Rainey WE, Ann Word RA: Human Myometrial Gene Expression Before and During Parturition. Biol Reprod. 2005, 72: 707-719. 10.1095/biolreprod.104.032979.CrossRefPubMed
4.
go back to reference Europe-Finner GN, Phaneuf S, Watson SP, López Bernal A: Identification and expression of G-proteins in human myometrium : up-regulation of Gαs in pregnancy. Endocrinology. 1993, 132: 2484-2490. 10.1210/en.132.6.2484.PubMed Europe-Finner GN, Phaneuf S, Watson SP, López Bernal A: Identification and expression of G-proteins in human myometrium : up-regulation of Gαs in pregnancy. Endocrinology. 1993, 132: 2484-2490. 10.1210/en.132.6.2484.PubMed
5.
go back to reference Brodt-Eppley J, Myatt L: Prostaglandin receptors in lower segment myometrium during gestation and labor. Obstet Gynecol. 1999, 93 (1): 89-93. 10.1016/S0029-7844(98)00378-0.CrossRefPubMed Brodt-Eppley J, Myatt L: Prostaglandin receptors in lower segment myometrium during gestation and labor. Obstet Gynecol. 1999, 93 (1): 89-93. 10.1016/S0029-7844(98)00378-0.CrossRefPubMed
6.
go back to reference Matlin AJ, Clark F, Smith CWJ: Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol. 2005, 6: 386-398. 10.1038/nrm1645.CrossRefPubMed Matlin AJ, Clark F, Smith CWJ: Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol. 2005, 6: 386-398. 10.1038/nrm1645.CrossRefPubMed
7.
go back to reference Pollard AJ, Sparey C, Krainer AR, Robson SC, Europe-Finner GN: Spatio-temporal expression of the trans-acting splicing factors SF2/ASF and hnRNPA1/A1B in the myometrium of the pregnant human uterus: a molecular mechanism for regulating regional isoform expression in vivo. J Clin Endocrinol Metab. 2000, 85: 1928-1936. 10.1210/jc.85.5.1928.PubMed Pollard AJ, Sparey C, Krainer AR, Robson SC, Europe-Finner GN: Spatio-temporal expression of the trans-acting splicing factors SF2/ASF and hnRNPA1/A1B in the myometrium of the pregnant human uterus: a molecular mechanism for regulating regional isoform expression in vivo. J Clin Endocrinol Metab. 2000, 85: 1928-1936. 10.1210/jc.85.5.1928.PubMed
8.
go back to reference Mayeda A, Krainer AR: Modulation of exon skipping and inclusion by heterogenous nuclear ribonuclearprotein A1 and pre-mRNA splicing factor SF2/ASF. Cell. 1993, 68: 365-375. 10.1016/0092-8674(92)90477-T.CrossRef Mayeda A, Krainer AR: Modulation of exon skipping and inclusion by heterogenous nuclear ribonuclearprotein A1 and pre-mRNA splicing factor SF2/ASF. Cell. 1993, 68: 365-375. 10.1016/0092-8674(92)90477-T.CrossRef
9.
go back to reference Pollard AJ, Krainer AR, Robson SC, Europe-Finner GN: Alternative splicing of the adenylyl cyclase stimulatory G-protein Gαs is regulated by SF2/ASF and hnRNP A1 in vivo and involves the use of an unusual 3' TG acceptor splice site. J Biol Chem. 2002, 277: 15241-15251. 10.1074/jbc.M109046200.CrossRefPubMed Pollard AJ, Krainer AR, Robson SC, Europe-Finner GN: Alternative splicing of the adenylyl cyclase stimulatory G-protein Gαs is regulated by SF2/ASF and hnRNP A1 in vivo and involves the use of an unusual 3' TG acceptor splice site. J Biol Chem. 2002, 277: 15241-15251. 10.1074/jbc.M109046200.CrossRefPubMed
10.
go back to reference Europe-Finner GN, Phaneuf S, Tolkovsky AM, Watson SP, López Bernal A: Down-regulation of G alpha s in human myometrium in term and preterm labor: a mechanism for parturition. J Clin Endocrinol Metab. 1994, 79 (6): 1835-9. 10.1210/jc.79.6.1835.PubMed Europe-Finner GN, Phaneuf S, Tolkovsky AM, Watson SP, López Bernal A: Down-regulation of G alpha s in human myometrium in term and preterm labor: a mechanism for parturition. J Clin Endocrinol Metab. 1994, 79 (6): 1835-9. 10.1210/jc.79.6.1835.PubMed
11.
go back to reference Price SA, López Bernal A: Uterine Quiescence:The role of cyclic AMP. Exp Physiol. 2001, 86.2: 265-272. 10.1113/eph8602182.CrossRef Price SA, López Bernal A: Uterine Quiescence:The role of cyclic AMP. Exp Physiol. 2001, 86.2: 265-272. 10.1113/eph8602182.CrossRef
12.
go back to reference Price SA, Pochun I, Phaneuf S, López Bernal A: Adenylyl cyclase isoforms in pregnant and non-pregnant human myometrium. J Endocrinol. 2000, 164: 21-30. 10.1677/joe.0.1640021.CrossRefPubMed Price SA, Pochun I, Phaneuf S, López Bernal A: Adenylyl cyclase isoforms in pregnant and non-pregnant human myometrium. J Endocrinol. 2000, 164: 21-30. 10.1677/joe.0.1640021.CrossRefPubMed
13.
go back to reference Bailey J, Philips R, Pollard AJ, Gilmore K, Robson SC, Europe-Finner GN: Characterisation and functional analysis of CREM and ATF2 isoforms in the human myometrium during fetal maturation: identification of a novel ATF2 species with potent trans-activation properties. J Clin Endocrinol Metab. 2002, 87 (4): 1717-28. 10.1210/jc.87.4.1717.CrossRefPubMed Bailey J, Philips R, Pollard AJ, Gilmore K, Robson SC, Europe-Finner GN: Characterisation and functional analysis of CREM and ATF2 isoforms in the human myometrium during fetal maturation: identification of a novel ATF2 species with potent trans-activation properties. J Clin Endocrinol Metab. 2002, 87 (4): 1717-28. 10.1210/jc.87.4.1717.CrossRefPubMed
14.
go back to reference Tyson-Capper AJ, Bailey J, Krainer AR, Robson SC, Europe-Finner GN: The switch in alternative splicing of cyclic AMP response element modulator protein CREMτ2α (activator) to CREMα (repressor) in human myometrial cells is mediated by srp40. J Biol Chem. 2005, 280 (41): 34521-9. 10.1074/jbc.M505344200.CrossRefPubMed Tyson-Capper AJ, Bailey J, Krainer AR, Robson SC, Europe-Finner GN: The switch in alternative splicing of cyclic AMP response element modulator protein CREMτ2α (activator) to CREMα (repressor) in human myometrial cells is mediated by srp40. J Biol Chem. 2005, 280 (41): 34521-9. 10.1074/jbc.M505344200.CrossRefPubMed
15.
go back to reference Sazani P, Vacek MM, Kole R: Short-term and long-term modulation of gene expression by antisense therapeutics. Curr Opin Biotechnol. 2002, 13: 468-472. 10.1016/S0958-1669(02)00366-X.CrossRefPubMed Sazani P, Vacek MM, Kole R: Short-term and long-term modulation of gene expression by antisense therapeutics. Curr Opin Biotechnol. 2002, 13: 468-472. 10.1016/S0958-1669(02)00366-X.CrossRefPubMed
16.
go back to reference Sazani P, Kole R: Therapeutic potential of antisense oligonucleotides as modulators of alternative splicing. J Clin Invest. 112: 481-486. 10.1172/JCI200319547. Sazani P, Kole R: Therapeutic potential of antisense oligonucleotides as modulators of alternative splicing. J Clin Invest. 112: 481-486. 10.1172/JCI200319547.
17.
go back to reference Mann CJ, Honeyman K, Cheng AJ: Antisense-induced exon skipping and synthesis of the dystrophin gene in the mdx mouse. Proc Natl Acad Sci USA. 2001, 98: 42-46. 10.1073/pnas.011408598.PubMedCentralCrossRefPubMed Mann CJ, Honeyman K, Cheng AJ: Antisense-induced exon skipping and synthesis of the dystrophin gene in the mdx mouse. Proc Natl Acad Sci USA. 2001, 98: 42-46. 10.1073/pnas.011408598.PubMedCentralCrossRefPubMed
18.
go back to reference Tyson-Capper AJ, Europe-Finner GN: Novel targeting Of COX-2 pre-mRNA using antisense morpholino oligonucleotides: Suppression of COX-2 activity in human amnion-derived WISH and myometrial cells. Mol Pharmacol. 2006, 69: 796-804.PubMed Tyson-Capper AJ, Europe-Finner GN: Novel targeting Of COX-2 pre-mRNA using antisense morpholino oligonucleotides: Suppression of COX-2 activity in human amnion-derived WISH and myometrial cells. Mol Pharmacol. 2006, 69: 796-804.PubMed
Metadata
Title
Alternative splicing: an important mechanism for myometrial gene regulation that can be manipulated to target specific genes associated with preterm labour
Author
Alison Jane Tyson-Capper
Publication date
01-06-2007
Publisher
BioMed Central
Published in
BMC Pregnancy and Childbirth / Issue Special Issue 1/2007
Electronic ISSN: 1471-2393
DOI
https://doi.org/10.1186/1471-2393-7-S1-S13

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