Mechanical stretch and progesterone differentially regulate activator protein-1 transcription factors in primary rat myometrial smooth muscle cells

Mitchell, Jennifer A.; Shynlova, Oksana; Langille, B. Lowell; Lye, Stephen J.

doi:10.1152/ajpendo.00275.2003

Cited by 42 publications

(19 citation statements)

References 34 publications

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“…The Fos genes are immediate or early genes, and can be rapidly activated in response to intracellular signaling cascades with no intervening protein synthesis (25,32). Both c-Fos and FosB have previously been shown to be mechanosensitive at both mRNA and protein levels, and in different types of cells (both in vitro and in vivo), including tenocytes, osteoblasts, pulmonary epithelial cells, periodontal ligament cells, smooth muscle cells, bone marrow cells, chondrocytes, and fibroblasts (14,17,19,24,25,29,32,35,36,40,47,49). The increase in c-Fos gene expression in osteoblast-like cells has also been shown to occur more rapidly and reach higher levels after tensile loading compared with compressive loading (25).…”

Section: Fosb and C-fos: Transcription Factors Involved In Proliferatmentioning

confidence: 99%

Primary gene response to mechanical loading in healing rat Achilles tendons

Eliasson

Andersson

Hammerman

et al. 2013

Journal of Applied Physiology

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Eliasson P, Andersson T, Hammerman M, Aspenberg P. Primary gene response to mechanical loading in healing rat Achilles tendons. J Appl Physiol 114: 1519 -1526, 2013. First published March 21, 2013 doi:10.1152/japplphysiol.01500.2012.-Loading can stimulate tendon healing. In healing rat Achilles tendons, we have found more than 150 genes upregulated or downregulated 3 h after one loading episode. We hypothesized that these changes were preceded by a smaller number of regulatory genes and thus performed a microarray 15 min after a short loading episode, to capture the primary response to loading. We transected the Achilles tendon of 54 rats and allowed them to heal. The hind limbs were unloaded by tail-suspension during the entire experiment, except during the loading episode. The healing tendon tissue was analyzed by mechanical testing, microarray, and quantitative real-time polymerase chain reaction (qRT-PCR). Mechanical testing showed that 5 min of loading each day for 4 days created stronger tissue. The microarray analysis after one loading episode identified 15 regulated genes. Ten genes were analyzed in a repeat experiment with new rats using qRT-PCR. This confirmed the increased expression of four genes: early growth response 2 (Egr2), c-Fos, FosB, and regulation of G protein signaling 1 (Rgs1). The other genes were unaltered. We also analyzed the expression of early growth response 1 (Egr1), which is often coregulated with c-Fos or Egr2, and found that this was also increased after loading. Egr1, Egr2, c-Fos, and FosB are transcription factors that can be triggered by numerous stimuli. However, Egr1 and Egr2 are necessary for normal tendon development, and can induce ectopic expression of tendon markers. The five regulated genes appear to constitute a general activation machinery. The further development of gene regulation might depend on the tissue context. tail-suspension; treadmill walking; tendon repair; early growth response; microarray TENDONS ADAPT TO CHANGES IN mechanical loading (5,6,20), and sufficient mechanical stimulation appears to be required for appropriate healing of ruptured tendons (11,12,34). Yet there is always a risk of re-rupture if too much loading is applied after injury. In rats, short daily episodes of loading of an otherwise unloaded healing Achilles tendon increases the strength of the healing tissue (1, 9, 10). In human patients, early weight bearing after surgical repair of Achilles tendon ruptures has been suggested to improve the clinical outcome (26,43).Mechanical loading stimulates collagen expression during tendon healing (11). At least in rats, it results in an increased cross-sectional area of the callus tissue, leading to an increase in strength (11). The mechanisms behind the effect of mechanical stimulation are not fully understood, and the signaling pathways involved in tendon mechano-transduction in vivo are not well described. We previously studied the changes in gene expression that arise when an unloaded healing tendon is exposed to 30 min of loading (10). We ...

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Section: Fosb and C-fos: Transcription Factors Involved In Proliferatmentioning

confidence: 99%

Primary gene response to mechanical loading in healing rat Achilles tendons

Eliasson

Andersson

Hammerman

et al. 2013

Journal of Applied Physiology

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“…Before exposure to mechanical stretch, the confluent cells were incubated for 24 h in serum-free DMEM. We have previously reported that 1 M P4, a dose mimicking the levels present during late pregnancy, both delayed and reduced the stretch induction of several members of the AP-1 family of genes in uterine SMCs (30). Thus, for the P4 studies, cell monolayers were preincubated with hormone (1 M; Sigma-Aldrich) for 24 h before the application of stretch.…”

Section: Application Of Static Stretchmentioning

confidence: 99%

Monocyte Chemoattractant Protein-1 (CCL-2) Integrates Mechanical and Endocrine Signals That Mediate Term and Preterm Labor

Shynlova

Tsui

Dorogin

et al. 2008

The Journal of Immunology

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143

126

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Recent evidence suggests that leukocytes infiltrate uterine tissues at or around the time of parturition, implicating inflammation as a key mechanism of human labor. MCP-1 (also known as C-C chemokine motif ligand 2, CCL-2) is a proinflammatory cytokine that is up-regulated in human myometrium during labor. Myometrium was collected from pregnant rats across gestation and at labor. Total RNA and proteins were subjected to real-time PCR and ELISA, respectively. Ccl-2 gene and protein expression was significantly up-regulated in the gravid rat myometrium before and during labor, which might suggest that it is regulated positively by mechanical stretch of the uterus imposed by the growing fetus and negatively by physiological withdrawal of progesterone (P4). We confirmed in vivo that: 1) administration of P4 receptor antagonist RU486 induced an increase in Ccl-2 mRNA and preterm labor, whereas 2) artificial maintenance of elevated P4 levels at late gestation caused a significant decrease in gene expression and blocked labor; 3) Ccl-2 was elevated specifically in the gravid horn of unilaterally pregnant rats suggesting that mechanical strain imposed by the growing fetus controls its expression in the myometrium; 4) in vitro static mechanical stretch of primary rat myometrial smooth muscle cells (25% elongation) induced a release of Ccl-2 protein, which was repressed by pretreatment with P4 (1 μM); and 5) stretch enhanced their monocyte chemoattractant activity. These data indicate that Ccl-2 protein serves to integrate mechanical and endocrine signals contributing to uterine inflammation and the induction of labor and thus may represent a novel target for therapeutic prevention of preterm labor in humans.

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“…Myometrial tissue samples were collected from nonpregnant rats and pregnant rats on gestational d 6,8,10,12,14,15,17,19,21,22, and 23 (labor), as well as 1 and 4 d postpartum (n ϭ 4 for each time point) (Fig. 7D).…”

Section: Gestational Profile Of Myometrial P54nrb Protein In Ratmentioning

confidence: 99%

“…Biochemically, this transformation is characterized by upregulation in the expression and function of genes encoding a cassette of labor-associated proteins such as the gap junction connexin 43 (Gja1) (3), ion channels (4), and stimulatory uterotonin receptors (5,6). It is known that progesterone signaling represses the expression of several of these labor genes (7)(8)(9). Derepression of the transcription of these labor genes at term can be achieved either by a decline in circulating progesterone levels or by blockade of PR function.…”

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confidence: 99%

p54nrb Is a Transcriptional Corepressor of the Progesterone Receptor that Modulates Transcription of the Labor-Associated Gene, Connexin 43 (Gja1)

Dong

Shynlova

et al. 2009

Molecular Endocrinology

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The progesterone receptor (PR) plays important roles in the establishment and maintenance of pregnancy. By dynamic interactions with coregulators, PR represses the expression of genes that increase the contractile activity of myometrium and contribute to the initiation of labor. We have previously shown that PTB-associated RNA splicing factor (PSF) can function as a PR corepressor. In this report, we demonstrated that the PSF heterodimer partner, p54nrb (non-POU-domain-containing, octamer binding protein), can also function as a transcription corepressor, independent of PSF. p54nrb Interacts directly with PR independent of progesterone. In contrast to PSF, p54nrb neither enhances PR protein degradation nor blocks PR binding to DNA. Rather, p54nrb recruits mSin3A through its N terminus to the PR-DNA complex, resulting in an inhibition of PR-mediated transactivation of the progesterone-response element-luciferase reporter gene. PR also repressed transcription of the connexin 43 gene (Gja1), an effect dependent on the presence of an activator protein 1 site within the proximal Gja1 promoter. Mutation of this site abolished PR-mediated repression and decreased the recruitment of PR and p54nrb onto the Gja1 promoter. Furthermore, knockdown p54nrb expression by small interfering RNA alleviated PR-mediated repression on Gja1 transcription, whereas overexpression of p54nrb enhanced it. In the physiological context of pregnancy, p54nrb protein levels decrease with the approach of labor in the rat myometrium. We conclude that p54nrb is a transcriptional corepressor of PR. Decreased expression of p54nrb at the time of labor may act to derepress PR-mediated inhibition on connexin 43 expression and contribute to the initiation of labor.

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Mechanical stretch and progesterone differentially regulate activator protein-1 transcription factors in primary rat myometrial smooth muscle cells

Abstract: . Mechanical stretch and progesterone differentially regulate activator protein-1 transcription factors in primary rat myometrial smooth muscle cells. Am J Physiol Endocrinol Metab

Cited by 42 publications

References 34 publications

Primary gene response to mechanical loading in healing rat Achilles tendons

Primary gene response to mechanical loading in healing rat Achilles tendons

Monocyte Chemoattractant Protein-1 (CCL-2) Integrates Mechanical and Endocrine Signals That Mediate Term and Preterm Labor

p54nrb Is a Transcriptional Corepressor of the Progesterone Receptor that Modulates Transcription of the Labor-Associated Gene, Connexin 43 (Gja1)

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