Estrogen Downregulates the Number of Caveolae and the Level of Caveolin in Uterine Smooth Muscle

Turi, Ágnes

doi:10.1006/cbir.2001.0769

Cited by 46 publications

(45 citation statements)

References 41 publications

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“…It is possible that this complex influences PI3K/Akt activity. In vivo, estrogen decreases the number of caveolae in uterine smooth muscle, an effect that was blocked by ICI 182 780 [60]. In support of a relationship between E 2 and caveolin, E 2 differently influenced caveolin production in MCF-7 cells and VSMCs [56].…”

Section: Estrogen Coupling To Enos Might Involvementioning

confidence: 88%

Estrogen action and cytoplasmic signaling cascades. Part I: membrane-associated signaling complexes

Segars

Driggers

2002

Trends in Endocrinology & Metabolism

168

102

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Remarkable progress in recent years has suggested that estrogen action in vivo is complex and often involves activation of cytoplasmic signaling cascades in addition to genomic actions mediated directly through estrogen receptors α and β. Rather than a linear response mediated solely through estrogen-responsive DNA elements, in vivo estrogen might simultaneously activate distinct signaling cascades that function as networks to coordinate tissue responses to estrogen. This complex signaling system provides for exquisite control and plasticity of response to estrogen at the tissue level, and undoubtedly contributes to the remarkable tissue-specific responses to estrogens. In part I of this series, we summarize cytoplasmic signaling modules involving estrogen or estrogen receptors, with particular focus on recently described membrane-associated signaling complexes.Knowledge of the molecular mechanism of estrogen action has evolved rapidly during the past two decades. It is now accepted that two proteins serve as receptors for 17β estradiol (E 2 ), estrogen receptors α and β (ERα, ERβ). These receptors function as ligand-dependent transcription factors to increase gene transcription from promoters by direct binding of the receptor to specific DNA target sequences, designated estrogen response elements (EREs). Association of receptors with the gene transcription machinery involves essential coregulatory proteins that contribute to estrogen action and that can enhance or repress ER action (see Refs [1][2][3]). The importance of this signaling pathway in vivo has been substantiated using several approaches, including targeted gene disruption (knockout) in mice [4][5][6][7][8]. Within the ER proteins, there are two activating functions corresponding to the N-terminus (AF-1) or ligand-binding region (AF-2) of the molecule [9] (and Refs therein). In addition, ER function is modified by its phosphorylation [10,11]. The genomic actions of E 2 proceeding through augmentation or repression of ERE-containing promoters by ERs α and β have been designated the classic pathway of estrogen action [12]. In addition, ER acts through AP-1 and SP-1 to affect transcription.* segarsj@mail.nih.gov. In spite of the clarity with which the ER has been shown to act as a transcription factor, it has been apparent for several years that not all physiological effects of E 2 are accomplished through a direct effect on gene transcription [13]. Definition of the classic estrogen-signaling pathway highlighted the fact that, in many instances, another signaling pathway(s) involving cytoplasmic proteins, growth factors and/or membrane-initiated responses contributed to estrogen action (reviewed in Refs [14][15][16][17][18]). In Part I of this review, we focus on membraneassociated estrogen action, particularly cellular responses observed within minutes of estrogen exposure. Part II (to be published in the December issue of TEM) covers cytoplasmic cascades initiated by growth factors, and involvement of the ER in second messenger signaling casc...

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Section: Estrogen Coupling To Enos Might Involvementioning

confidence: 88%

Estrogen action and cytoplasmic signaling cascades. Part I: membrane-associated signaling complexes

Segars

Driggers

2002

Trends in Endocrinology & Metabolism

168

102

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“…Recently, studies of the regulation of receptor signaling in endothelial caveolae have suggested their role as calcium sensors . Caveolae are richly expressed in smooth muscles, including myometrium (Kwan et al, 1986), and their numbers are regulated (Turi et al, 2001). Perhaps the conundrum presented here can be resolved on the basis of the organization of receptor signaling in myometrium between detergent-insoluble glycolipid-rich domains, including rafts and caveolae (Anderson and Jacobson, 2002), and the soluble and myo-filamentous regions of the cell.…”

Section: Caveolar Signalingmentioning

confidence: 89%

Regulation of Uterine Function: a Biochemical Conundrum in the Regulation of Smooth Muscle Relaxation

Buxton

2004

Molecular Pharmacology

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Premature birth accounts for the majority of fetal morbidity and mortality in the developed world and is disproportionately represented in some populations, such as African Americans in the United States. The costs associated with prematurity are staggering in both monetary and human terms. Present therapeutic approaches for the treatment of labor leading to preterm delivery are inadequate and our understanding of the regulation of myometrial smooth muscle contraction-relaxation is incomplete. The ability of nitric oxide to relax smooth muscle has led to an interest in employing nitric oxide-donors in the treatment of preterm labor. Fundamental differences exist, however, in the regulation of uterine smooth muscle relaxation and that of other smooth muscles and constitute a conundrum in our understanding. We review the evidence that nitric oxide-mediated relaxation of myometrial smooth muscle, unlike vascular or gastrointestinal smooth muscle, is independent of global elevation of cyclic guanosine 5Ј-monophosphate. Applying our current understanding of microdomain signaling and taking clues from genomic studies of pregnancy, we offer a framework in which to view the apparent conundrum and suggest testable hypotheses of uterine relaxation signaling that can explain the mechanistic distinctions. We propose that understanding these mechanistic distinctions in myometrium will reveal molecular targets that are unique and thus may be explored as therapeutic targets in the development of new uterine smooth musclespecific tocolytics.

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“…The gene for caveolin 2 (CAV2) was up-regulated by ATF2; caveolin expression in the myometrium of the pregnant rat is known to be suppressed in the first half of pregnancy, after which it increases up to delivery, increasing the number of caveolae present in myometrial cells (Turi et al 2001). This has been shown to be dependent upon levels of oestrogen and progesterone.…”

Section: Discussionmentioning

confidence: 99%

Identification of human myometrial target genes of the c-Jun NH2-terminal kinase (JNK) pathway: the role of activating transcription factor 2 (ATF2) and a novel spliced isoform ATF2-small

Bailey¹,

Europe‐Finner²

2005

Journal of Molecular Endocrinology

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Activating transcription factor 2 (ATF2), a ubiquitously expressed member of the basic region leucine zipper (bZIP) family of transcription factors activated by mitogen activated protein kinase (MAPK) pathways, is important in the mediation of cellular stress responses, development and transformation. We have previously reported the differential expression of active ATF2 in the human myometrium throughout pregnancy and labour, and identified and partially characterized a novel splice variant ATF2-small (ATF2-sm). To further understand the role of these factors in the myometrium, we have used gene microarrays to define the target genes in cultured myometrial cells stably-transfected with ATF2 and ATF2-sm cDNAs. Many of the genes identified appear to have potential roles in regulating myometrial function and include proteins involved in G-protein receptor signalling, cytokine signalling, transcriptional regulation, cell-cycle control, formation of the extracellular matrix and cytoskeletal architecture. ATF2 was found to affect the expression of 204 genes; 113 being up-regulated and 91 down-regulated whereas the novel ATF2-sm factor altered the expression of 55 genes; expression was increased in 29 cases and decreased in 26. A further 25 genes affected by ATF2-sm were identified by suppression subtractive hybridisation (SSH). Notably, the genes affected by ATF2 and ATF2-sm appear to belong to discrete groups: only two genes were affected by both factors.

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Estrogen Downregulates the Number of Caveolae and the Level of Caveolin in Uterine Smooth Muscle

Cited by 46 publications

References 41 publications

Estrogen action and cytoplasmic signaling cascades. Part I: membrane-associated signaling complexes

Estrogen action and cytoplasmic signaling cascades. Part I: membrane-associated signaling complexes

Regulation of Uterine Function: a Biochemical Conundrum in the Regulation of Smooth Muscle Relaxation

Identification of human myometrial target genes of the c-Jun NH2-terminal kinase (JNK) pathway: the role of activating transcription factor 2 (ATF2) and a novel spliced isoform ATF2-small

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