This pathway illustrates signaling networks implicated in uterine muscle contraction at labor and quiescence throughout gestation (pregnancy). The muscle of the uterus, responsible for contractile activity is the myometrium. Genes in this pathway are either transcribed in myometrial muscle cells or act upon the myometrium to regulate contraction. The left half of this pathway illustrates pathways of myometrial relaxation that are active throughout normal gestation. These signaling events act to suppress coordinated contractions to prevent the early onset of labor at term, largely via activation of the adenylyl-cyclase thrhough G-protein coupled receptors. On the right side of this pathway are signaling componets involved in the activation of uterine contractions at labor, in particular, activation of calcium mobilization via Oxytocin mediated binding to the Oxytocin G-protein coupled receptor. Additional genes implicated in this pathway, based on microarray expression profiling of gestation, term and postpartum of term mice are also included (e.g., Guca2b, Rdc1, Edg2) have also been included. For a detailed description of this pathway see: http://genomebiology.com/2005/6/2/R12.
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HomologyConvert
This pathway was inferred from Homo sapiens pathway WP289(r21289) with a 90% conversion rate.
Salomonis N, Cotte N, Zambon AC, Pollard KS, Vranizan K, Doniger SW, Dolganov G, Conklin BR; ''Identifying genetic networks underlying myometrial transition to labor.''; Genome Biol, 2005 PubMedEurope PMCScholia
Aggelidou E, Hillhouse EW, Grammatopoulos DK; ''Up-regulation of nitric oxide synthase and modulation of the guanylate cyclase activity by corticotropin-releasing hormone but not urocortin II or urocortin III in cultured human pregnant myometrial cells.''; Proc Natl Acad Sci U S A, 2002 PubMedEurope PMCScholia
Identification of a GABP alpha/beta binding site involved in the induction of oxytocin receptor gene expression in human breast cells, potentiation by c-Fos/c-Jun.
Identification of a GABP alpha/beta binding site involved in the induction of oxytocin receptor gene expression in human breast cells, potentiation by c-Fos/c-Jun.
Structure, characterization, and expression of the rat oxytocin receptor gene.
Rozen F, Russo C, Banville D, Zingg HH PMID: 7816817 quote: The presence of APREs in the OTR gene promoter suggests that the acute induction of OTR expression at the onset of parturition may be a phenomenon mechanistically similar to the fast induction of acute phase response genes. This notion is strengthened by the observation that the uterus is populated by macrophages and other specific lymphocytes (19,20). Specifically, at term, nearly half of the decidual cells are of bone marrow origin (20). IL-1beta released from macrophages stimulates the production and release of IL-6 by uterine stromal cells (21,22). Moreover, IL- is a central pathophysiological mediator of infection-induced premature delivery (23), and preterm delivery can be prevented by an IL-1 antagonist in mice (24). We speculate that under physiological as well as phathophysiological conditions, inflammatory cytokines are important inducers of labor and that this mechanism involves the cytokine-induced transcriptional activation of the OTR gene. :end quote
19. Hunt, J.S. (1994) Biol. Reprod. 50, 461-466
20. Vince, G.S., et al. (1990) J. Immunol. Methods 132, 181-189.
21. Tabibzadeh, S. (1991) Endocr. Rev, 12, 272-290.
22. Dudley, D.Jl, et. Al. (1992) J. Clin. Endocrinol. Metab. 74, 884-889
23. Romero, R., et. Al, Am. J. Obstet. Gynecol. 167, 863-872.
Structure, characterization, and expression of the rat oxytocin receptor gene.
Rozen F, Russo C, Banville D, Zingg HH PMID: 7816817 quote: The presence of APREs in the OTR gene promoter suggests that the acute induction of OTR expression at the onset of parturition may be a phenomenon mechanistically similar to the fast induction of acute phase response genes. This notion is strengthened by the observation that the uterus is populated by macrophages and other specific lymphocytes (19,20). Specifically, at term, nearly half of the decidual cells are of bone marrow origin (20). IL-1beta released from macrophages stimulates the production and release of IL-6 by uterine stromal cells (21,22). Moreover, IL- is a central pathophysiological mediator of infection-induced premature delivery (23), and preterm delivery can be prevented by an IL-1 antagonist in mice (24). We speculate that under physiological as well as phathophysiological conditions, inflammatory cytokines are important inducers of labor and that this mechanism involves the cytokine-induced transcriptional activation of the OTR gene. :end quote
19. Hunt, J.S. (1994) Biol. Reprod. 50, 461-466
20. Vince, G.S., et al. (1990) J. Immunol. Methods 132, 181-189.
21. Tabibzadeh, S. (1991) Endocr. Rev, 12, 272-290.
22. Dudley, D.Jl, et. Al. (1992) J. Clin. Endocrinol. Metab. 74, 884-889
23. Romero, R., et. Al, Am. J. Obstet. Gynecol. 167, 863-872.
OMIM: Inoue et al. (1994) demonstrated that the US-2 element in the promoter of the human oxytocin receptor gene (OXTR; 167055) binds specifically nuclear proteins from human myometrium at parturition. Using the US-2 element in a yeast 1-hybrid system to screen a human myometrium cDNA library, Kimura et al. (1999) isolated a full-length cDNA encoding the homolog of chicken MafF. Human MAFF encodes a deduced 164-amino acid protein with a predicted molecular mass of 17.8 kD. Like other small MAF proteins (e.g., MAFG, 602020), it contains an extended leucine zipper structure and lacks an N-terminal transactivating domain. Northern blot analysis showed a strong 2.6-kb signal in mRNA from term myometrium and from kidney, but not from nonpregnant myometrium. The MAFF protein is also preferentially expressed in term myometrium. The authors concluded that MAFF plays a role in OXTR gene upregulation at term.
Localization of regulatory protein binding sites in the proximal region of human myometrial connexin 43 gene.
Echetebu CO, Ali M, Izban MG, MacKay L, Garfield RE. PMID: 10421804
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Hoare S, Copland JA, Wood TG, Jeng YJ, Izban MG, Soloff MS.
PMID: 10218980Hoare S, Copland JA, Wood TG, Jeng YJ, Izban MG, Soloff MS.
PMID: 10218980Sladek SM, Westerhausen-Larson A, Roberts JM.
PMID: 10377025Rozen F, Russo C, Banville D, Zingg HH PMID: 7816817 quote: The presence of APREs in the OTR gene promoter suggests that the acute induction of OTR expression at the onset of parturition may be a phenomenon mechanistically similar to the fast induction of acute phase response genes. This notion is strengthened by the observation that the uterus is populated by macrophages and other specific lymphocytes (19,20). Specifically, at term, nearly half of the decidual cells are of bone marrow origin (20). IL-1beta released from macrophages stimulates the production and release of IL-6 by uterine stromal cells (21,22). Moreover, IL- is a central pathophysiological mediator of infection-induced premature delivery (23), and preterm delivery can be prevented by an IL-1 antagonist in mice (24). We speculate that under physiological as well as phathophysiological conditions, inflammatory cytokines are important inducers of labor and that this mechanism involves the cytokine-induced transcriptional activation of the OTR gene. :end quote
19. Hunt, J.S. (1994) Biol. Reprod. 50, 461-466 20. Vince, G.S., et al. (1990) J. Immunol. Methods 132, 181-189. 21. Tabibzadeh, S. (1991) Endocr. Rev, 12, 272-290. 22. Dudley, D.Jl, et. Al. (1992) J. Clin. Endocrinol. Metab. 74, 884-889 23. Romero, R., et. Al, Am. J. Obstet. Gynecol. 167, 863-872.
Rozen F, Russo C, Banville D, Zingg HH PMID: 7816817 quote: The presence of APREs in the OTR gene promoter suggests that the acute induction of OTR expression at the onset of parturition may be a phenomenon mechanistically similar to the fast induction of acute phase response genes. This notion is strengthened by the observation that the uterus is populated by macrophages and other specific lymphocytes (19,20). Specifically, at term, nearly half of the decidual cells are of bone marrow origin (20). IL-1beta released from macrophages stimulates the production and release of IL-6 by uterine stromal cells (21,22). Moreover, IL- is a central pathophysiological mediator of infection-induced premature delivery (23), and preterm delivery can be prevented by an IL-1 antagonist in mice (24). We speculate that under physiological as well as phathophysiological conditions, inflammatory cytokines are important inducers of labor and that this mechanism involves the cytokine-induced transcriptional activation of the OTR gene. :end quote
19. Hunt, J.S. (1994) Biol. Reprod. 50, 461-466 20. Vince, G.S., et al. (1990) J. Immunol. Methods 132, 181-189. 21. Tabibzadeh, S. (1991) Endocr. Rev, 12, 272-290. 22. Dudley, D.Jl, et. Al. (1992) J. Clin. Endocrinol. Metab. 74, 884-889 23. Romero, R., et. Al, Am. J. Obstet. Gynecol. 167, 863-872.
Sladek SM, Westerhausen-Larson A, Roberts JM.
PMID: 10377025Fernandez-Cobo M, Stewart D, Drujan D, De Maio A.
Division of Pediatric Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
PMID: 11255234Annotated Interactions
No annotated interactions