The further redefining of steroid-mediated signaling

Hammes, Stephen R.

doi:10.1073/pnas.0530224100

Cited by 73 publications

(43 citation statements)

References 39 publications

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“…Furthermore, this work demonstrates that comparison of temporal changes in gene expression and conventional toxicology parameters (uterine weight and histologic changes) can provide an understanding of the relationships between gene expression patterns and phenotypic change. E 2 can regulate transcription through a combination of at least two distinct signaling pathways: a) via activation of the nuclear transcription factors ER-α and ER-β (Hall et al 2001;McKenna and O'Malley 2002;Moggs and Orphanides 2001;Tremblay and Giguere 2002) and b) via extranuclear or "nongenomic" signaling events (Falkenstein et al 2000;Hammes 2003;Moggs et al 2003). The transcriptional responses to E 2 that we have defined here are likely to involve a combination of direct gene regulation by nuclear ERs and indirect gene regulation via extranuclear signaling pathways.…”

Section: Discussionmentioning

confidence: 93%

Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth

Moggs¹,

Tinwell²,

Spurway³

et al. 2004

Environ Health Perspect

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A major challenge in the emerging field of toxicogenomics is to define the relationships between chemically induced changes in gene expression and alterations in conventional toxicologic parameters such as clinical chemistry and histopathology. We have explored these relationships in detail using the rodent uterotrophic assay as a model system. Gene expression levels, uterine weights, and histologic parameters were analyzed 1, 2, 4, 8, 24, 48, and 72 hr after exposure to the reference physiologic estrogen 17β-estradiol (E 2 ). A multistep analysis method, involving unsupervised hierarchical clustering followed by supervised gene ontology-driven clustering, was used to define the transcriptional program associated with E 2 -induced uterine growth and to identify groups of genes that may drive specific histologic changes in the uterus. This revealed that uterine growth and maturation are preceded and accompanied by a complex, multistage molecular program. The program begins with the induction of genes involved in transcriptional regulation and signal transduction and is followed, sequentially, by the regulation of genes involved in protein biosynthesis, cell proliferation, and epithelial cell differentiation. Furthermore, we have identified genes with common molecular functions that may drive fluid uptake, coordinated cell division, and remodeling of luminal epithelial cells. These data define the mechanism by which an estrogen induces organ growth and tissue maturation, and demonstrate that comparison of temporal changes in gene expression and conventional toxicology end points can facilitate the phenotypic anchoring of toxicogenomic data.

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Section: Discussionmentioning

confidence: 93%

Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth

Moggs¹,

Tinwell²,

Spurway³

et al. 2004

Environ Health Perspect

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“…Several studies have shown the existence of a variety of distinct but poorly characterized, putative, membraneassociated, progesterone-binding proteins in different tissues and species, although other lines of evidence suggest that some of the non-genomic progesterone responses are either mediated by 'classical' GPCRs or involve cytoplasmic activation of the nuclear PR (Gerdes et al 1998, Boonyaratanakornkit et al 2001, Bramley et al 2002, Losel & Wehling 2003, Losel et al 2004, Peluso 2004, Thomas et al 2004. Therefore, the characterization of a bona fide mPR in the spotted sea trout and the subsequent cloning of three human homologues (mPR , and ) represented an important discovery that suggests new opportunities to unravel the interplay between genomic and non-genomic progesterone signalling (Hammes 2003, Zhu et al 2003a. It also makes it possible to determine whether impaired membrane progesterone signalling can be implicated in reproductive failure or pregnancy disorders.…”

Section: Discussionmentioning

confidence: 99%

Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues

Fernandes¹,

Pierron²,

Michalovich³

et al. 2005

Journal of Endocrinology

122

103

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Rapid non-genomic actions of progesterone are implicated in many aspects of female reproduction. Recently, three human homologues of the fish membrane progestin receptor (mPR) have been identified. We combined bioinformatic analysis with expression profiling to define further the role of these mPRs in human reproductive tissues. Sequence analysis confirmed that the mPRs belong to a larger, highly conserved family of proteins, termed 'progestin and adiponectin receptors' (PAQRs). A comparison of the expression of mPR transcripts with that of two related PAQR family members, PAQRIII and PAQRIX, in cycling endometrium and pregnancy tissues revealed markedly divergent expression levels and profiles. For instance, endometrial expression of mPR and and PAQRIX was cycle-dependent whereas the onset of parturition was associated with a marked reduction in myometrial mPR and transcripts. Interestingly, mPR and PAQRIX were most highly expressed in the placenta, and the tissue expression levels of both genes correlated inversely with that of the nuclear PR. Phylogenetic analysis demonstrated that PAQRIX belongs to the mPR subgroup of proteins. We also validated a polyclonal antibody raised against the carboxy-terminus of human mPR . Immunohistochemical analysis demonstrated more intense immunoreactivity in placental syncytiotrophoblasts than in endometrial glands or stroma. The data suggest important functional roles for mPR , and possibly PAQRIX, in specific reproductive tissues, particularly those that express low levels of nuclear PR.

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“…Evidence was cited that expression of GR mRNA from the 1A promoter was also found to correlate with a putative membrane-bound form of the GR (21). Membrane-specific progesterone receptors were recently cloned from the sea trout, yet were found to be genetically distinct from the nuclear progesterone receptor (36). We are unable to comment directly on the cellular location of the GR expressed and synthesized from the 1A promoter, other than the fact that thymocytes treated with or without GC in vivo displayed no expression of the 150-kDa species of the GR, which is considered to be the membrane-bound GR.…”

Section: Discussionmentioning

confidence: 99%

Expression of the Glucocorticoid Receptor from the 1A Promoter Correlates with T Lymphocyte Sensitivity to Glucocorticoid-Induced Cell Death

Purton

Monk

Liddicoat

et al. 2004

The Journal of Immunology

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Glucocorticoid (GC) hormones cause pronounced T cell apoptosis, particularly in immature thymic T cells. This is possibly due to tissue-specific regulation of the glucocorticoid receptor (GR) gene. In mice the GR gene is transcribed from five separate promoters designated: 1A, 1B, 1C, 1D, and 1E. Nearly all cells express GR from promoters 1B–1E, but the activity of the 1A promoter has only been reported in the whole thymus or lymphocyte cell lines. To directly assess the role of GR promoter use in sensitivity to glucocorticoid-induced cell death, we have compared the activity of the GR 1A promoter with GC sensitivity in different mouse lymphocyte populations. We report that GR 1A promoter activity is restricted to thymocyte and peripheral lymphocyte populations and the cortex of the brain. The relative level of expression of the 1A promoter to the 1B–1E promoters within a lymphocyte population was found to directly correlate with susceptibility to GC-induced cell death, with the extremely GC-sensitive CD4+CD8+ thymocytes having the highest levels of GR 1A promoter activity, and the relatively GC-resistant αβTCR+CD24int/low thymocytes and peripheral T cells having the lowest levels. DNA sequencing of the mouse GR 1A promoter revealed a putative glucocorticoid-response element. Furthermore, GR 1A promoter use and GR protein levels were increased by GC treatment in thymocytes, but not in splenocytes. These data suggest that tissue-specific differences in GR promoter use determine T cell sensitivity to glucocorticoid-induced cell death.

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The further redefining of steroid-mediated signaling

Cited by 73 publications

References 39 publications

Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth

Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth

Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues

Expression of the Glucocorticoid Receptor from the 1A Promoter Correlates with T Lymphocyte Sensitivity to Glucocorticoid-Induced Cell Death

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