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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is substantial interest in the effects of estrogen on the vascular wall, due to the marked gender difference in the incidence of clinically apparent coronary heart disease (CHD), when comparing premenopausal women with age-matched males. Recent randomized clinical trials unexpectedly failed to demonstrate a hormone replacement therapy (HRT) benefit for CHD secondary or primary prevention in postmenopausal women. There are several possible explanations for these findings, which have created a conundrum in light of the numerous potentially beneficial vascular effects of estrogen demonstrated at the cellular, molecular, and even animal model level. Clinical trials are ongoing, and the dissection of molecular pathways continues. Although estrogen receptors (ERs) are traditionally defined as ligand-activated transcriptional activators or repressors, a phenomenon certainly involved in some of estrogen's beneficial effects on vascular cells, we and others have recently demonstrated the presence of membrane-associated ERs in endothelial cells (EC), and that engagement of this subset of receptors may also contribute to the favorable molecular profile of the endothelium. In this review, we describe evidence for membrane-localized ERs in EC. We discuss features of their membrane targeting, and how they may differ from classical ERs. We also describe the rapid assembly of a membrane-associated molecular complex, comprised of ER, c-Src and the regulatory unit of phosphatidylinositol 3-kinase (PI3K), p85, in response to estrogen. Finally, we describe how this complex triggers sequential enzyme activation, involving endothelial nitric oxide synthase (eNOS), and consequent enhanced basal release of NO, a key modulator of vascular tone and 'healthy' blood vessels.
Steroids
PMID:Vascular cell signaling by membrane estrogen receptors. 1586 21

Progesterone receptor (PR) isoforms are dual functioning steroid hormone receptors, capable of activation of target gene transcription, and rapid stimulation of membrane-initiated intracellular signaling cascades. Herein we provided a retrospective of our recent work investigating the role of progestin-activated intracellular signaling pathways on cell cycle progression in breast cancer cell models. We show that progestin-induced S-phase entry and upregulation of selected target genes, including cyclin D1, are MAPK-dependent events. Further experiments conducted with mutant PRs defective in either the transcriptional response (PR-S294A) or activation of c-Src-dependent intracellular signaling to MAPKs (PR-mPro) confirmed that the proliferative response of breast cancer cells to progestins is largely dependent on the ability of PR to rapidly activate Erk 1/2 MAPKs. During progestin-stimulated cell cycle progression, elevated cdk2 levels and activity target multiple phosphorylation sites on PR. Phosphorylation of Ser400 augments PR nuclear localization and mediates increased PR transcriptional activity in the absence of hormone, while the cdk inhibitor, p27, reversed these effects. Together, our data illustrate the versatility of PR as regulatory signaling molecules that also act as sensors for multiple kinase pathways, and suggest that progestins influence changes in breast cancer cell gene expression and proliferation via integration of PR functions as both ligand-activated transcription factors and rapid initiators of intracellular signaling pathways.
Steroids
PMID:Integration of progesterone receptor mediated rapid signaling and nuclear actions in breast cancer cell models: role of mitogen-activated protein kinases and cell cycle regulators. 1586 25

Aldosterone is an important regulator of Na(+) and K(+) transport in the distal nephron modulating the surface expression of transporters through the action of the mineralocorticoid receptor as a ligand-dependent transcription factor. Aldosterone stimulates the rapid activation of protein kinase-based signalling cascades that modulate the genomic effects of the hormone. Evidence is accumulating about the multi-factorial regulation of the epithelial sodium channel (ENaC) by aldosterone. Recent published data suggests that the activation of a novel PKC/PKD signalling pathway through the c-Src-dependent trans-activation of epidermal growth factor receptor contributes to early ENaC trafficking in response to aldosterone.
Steroids 2008 Oct
PMID:Aldosterone-induced signalling and cation transport in the distal nephron. 1830 53

Human progesterone receptor (PR) contains a polyproline motif in the amino-terminal domain that interacts with the SH3 domain of Src and mediates rapid activation of c-Src and downstream MAPK (Erk-1/-2) independent of the transcriptional activity of PR. Forcedly target PR to different locations in the cell by use of mutations or tags for different cell compartments showed that progestin activation of Src/MAPK is mediated by PR outside the nucleus. No distinction could be made between the cytoplasm and cell membrane as the site of PR activation of Src. Therefore we can only conclude that this is an extra-nuclear action of PR. Interestingly, the B isoform of PR which is naturally distributed between cytoplasm and nucleus mediated progestin activation of Src/MAPK, whereas PR-A that is predominantly nuclear failed to do so indicating that the two PR isoforms have distinct abilities to mediate rapid activation of signaling pathways. Due to distinct cellular locations, progestin activation of Src/MAPK signaling can regulate selected target genes such as cyclin D1 (CCND1) that lack direct PR binding response elements (PREs). Progestin induction of CCND1 was observed in cells expressing PR-B but not PR-BDeltaSH3 or PR-A and induction in the presence of PR-B was dramatically reduced in the presence of inhibitors of Src or MAPK. In contrast progestin induction of Sgk (serum and glucocorticoid regulated kinase) gene, which contains a classical PRE, was observed with both PR isoforms as well as PR-BDeltaSH3 and was unaffected by Src and MAPK inhibitors. PR bound to enhancer region of Sgk in a progestin dependent manner as detected by chromatin co-immunoprecipitation (ChIP) whereas no PR binding to CCDN1 was observed. Consistent with CCND1 data, progestin stimulation of cell cycle progression was only observed in cells expressing PR-B but not cells expressing PR-BDeltaSH3 or PR-A. These results demonstrate the importance of PR activation of extra-nuclear signaling pathways in regulating selected target genes and cell cycle progression.
Steroids 2008 Oct
PMID:The role and mechanism of progesterone receptor activation of extra-nuclear signaling pathways in regulating gene transcription and cell cycle progression. 1832 50

The definition of estrogen's actions has expanded from transcriptional regulation to the rapid, membrane-initiated activation of numerous signal transduction cascades. Multiple biological effects of estrogen have been shown in numerous animals, cellular and molecular studies, which support the favorable effects of estrogen on vascular structure, function, and cell signaling. Work from several laboratories has shown that these effects are mediated by distinct forms of estrogen receptor (ER) alpha. This includes estrogen-stimulated rapid activation of endothelial nitric oxide synthase (eNOS), resulting in the elaboration of the athero-protective, angiogenesis-promoting product nitric oxide (NO). We have described the expression of ER46, an N-terminus truncated isoform of the ERalpha, in human endothelial cells (EC), and its critical role in membrane-initiated, rapid responses to 17beta-estradiol (E2). We have proposed an ER46-centered, eNOS activating molecular complex in human EC caveolar membranes, containing c-Src, phosphatidylinositol 3-kinase (PI3K), Akt and eNOS. Our previous studies support estrogen-induced rapid eNOS activation via a sequential c-Src/PI3K/Akt cascade in EC. In this review, we describe estrogen-induced, rapid, non-genomic actions in endothelium, driven by c-Src-ER46-caveolin-1 interactions, with consequent activation of eNOS. Amidst ongoing controversies in hormone replacement therapy, these molecular and cellular data, defining favorable estrogenic effects on the endothelium, provide a strong impetus to resolve these clinical questions.
Steroids 2008 Oct
PMID:Vascular cell signaling by membrane estrogen receptors. 1832 57

Both steroids and growth factors stimulate proliferation of steroid-dependent tumor cells, and interaction between these signaling pathways occurs at several levels. Steroid receptors are classified as ligand-activated transcription factors, and steps by which they activate target gene transcription are well understood. Several steroid responses have now been functionally linked to other intracellular signaling pathways, including c-Src or tyrosine kinase receptors. Steroids such as 17beta-estradiol (E2), via binding to cytoplasmic or membrane-associated receptors, were also shown to rapidly activate intracellular signaling cascades such as ERK, PI3K and STATs. These E2-stimulated phosphorylations can then contribute to altered tumor cell function. ER-positive breast cancer cells, in which proliferation is stimulated by E2 and suppressed by antiestrogens, have been of particular interest in dissecting nuclear and cytoplasmic roles of estrogen receptors (ER). In some cell contexts, ER interacts directly with the intracellular tyrosine kinase c-Src and other cytoplasmic signaling and adaptor molecules, such as Shc, PI3K, MNAR, and p130 Cas. Although the hierarchy among these associations is not known, it is clear that c-Src plays a fundamental role in both growth factor and E2-stimulated cell growth, and this may also require other growth factor receptors such as those for EGF or IGF-1. STAT transcription factors represent one pathway to integrate E2 cytoplasmic and nuclear signaling. STAT5 is phosphorylated in the cytoplasm at an activating tyrosine in response to E2 or EGF, and then is translocated to the nucleus to stimulate target gene transcription. E2 stimulates recruitment of STAT5 and ER to the promoter of several proliferative genes, and STAT5 knockdown prevents recruitment of either protein to these promoters. STAT5 activation by E2 in breast cancer cells requires c-Src and EGF receptor, and inhibition of c-Src or EGFR, or knockdown of STAT5, prevents E2 stimulation of several genes and breast cancer cell proliferation. Hyperactivation of the growth factor receptor-c-Src pathway can in some contexts decrease growth responses to E2, or render cells and tumors resistant to suppressive actions of endocrine therapies. Crosstalk between growth factors and steroids in both the cytoplasm and nucleus may thus have a profound impact on complex biological processes such as cell growth, and may play a significant role in the treatment of steroid-dependent breast cancers.
Steroids 2009 Jul
PMID:Novel actions of estrogen to promote proliferation: integration of cytoplasmic and nuclear pathways. 1899 36

Progesterone is an ovarian steroid hormone that is essential for normal breast development. The actions of progesterone are largely mediated through binding to its cognate steroid hormone receptor, the progesterone receptor (PR). PR isoforms exist in the nucleus and transcriptionally activate genes necessary for proliferation and survival (classical role). Cytoplasmic or membrane-associated PR exists in the cytoplasm where it participates in protein complexes with signaling molecules and other steroid hormone receptors capable of rapid activation of cytoplasmic protein kinase cascades. This review details the extra nuclear scaffolding actions of PR with c-Src and MEK1, the upstream components of MAP kinase modules.
Steroids 2009 Jul
PMID:Scaffolding actions of membrane-associated progesterone receptors. 1913 65

Activation of IGF-1R can activate metalloproteinases which release heparin-binding EGF (Hb-EGF) and lead to EGFR-dependent MAPK activation in certain tissues. We postulated that this pathway is operative in E(2)-induced MAPK activation in breast cancer tissues. As evidence, we showed that E(2) rapidly induced the phosphorylation of both IGF-1R and EGFR and that siRNA knockdown or selective inhibitors against either growth factor receptor inhibited E(2)-induced MAPK activation. The selective inhibitors or knockdown of either IGF-1R or EGFR significantly inhibited cell growth and reversed cell death protection induced by E(2) in MCF-7 cells. Our data support the conclusion that the IGF-1R acts upstream of EGFR in a linear pathway which mediates E(2) action on MAPK activation, cell growth stimulation and anti-apoptosis in breast cancer cells. During the process of development of tamoxifen resistance this pathway is up-regulated with increased sensitivity to activate EGFR for cell growth and protection against apoptosis. Surprisingly, translocation of ERalpha out of the nucleus into the cytoplasm, mediated by c-Src, occurs during development of resistance. This effect can be abrogated by administration of the c-Src inhibitor, PP2 which also restores sensitivity to tamoxifen.
Steroids 2009 Jul
PMID:Estrogen signals via an extra-nuclear pathway involving IGF-1R and EGFR in tamoxifen-sensitive and -resistant breast cancer cells. 1913 96

Progesterone receptors (PR) select and control genetic programs in the breast during normal mammary gland development, and progestin-driven processes contribute to the initiation and/or progression of breast cancer [Beral, V., 2003. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362, 419-427; Chlebowski, R.T., Hendrix, S.L., Langer, R.D., Stefanick, M.L., Gass, M., Lane, D., Rodabough, R.J., Gilligan, M.A., Cyr, M.G., Thomson, C.A., et al., 2003. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289, 3243-3253]. Throughout the mammalian life span, progesterone exerts varying biological consequences on the mammary epithelial compartment, from brief proliferative spurts that occur with each luteal phase of the menstrual cycle to the massive expansion of the pregnant gland in preparation for lactation [Brisken, C., Park, S., Vass, T., Lydon, J.P., O'Malley, B.W., Weinberg, R.A., 1998. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc. Natl. Acad. Sci. U.S.A. 95, 5076-5081; Ismail, P.M., Amato, P., Soyal, S.M., DeMayo, F.J., Conneely, O.M., O'Malley, B.W., Lydon, J.P., 2003. Progesterone involvement in breast development and tumorigenesis-as revealed by progesterone receptor "knockout" and "knockin" mouse models. Steroids 68, 779-787]. These processes, while important developmentally, can become deregulated in breast cancer, thereby contributing to unchecked proliferation, increased survival, and invasive behaviors. Recently, our lab has focused on the molecular mechanisms, including phosphorylation events, by which PRs select specific target genes in response to progestins and other mitogenic hormonal signals (i.e. EGF, heregulin). Herein, we discuss the actions of cytoplasmic signaling molecules such as c-Src and mitogen-activated protein kinases as key mediators of PR promoter selectivity.
 ...
PMID:Signaling inputs to progesterone receptor gene regulation and promoter selectivity. 1954 91

In hypertension or other forms of cardiovascular disease, the chronic activation of the renin-angiotensin-aldosterone system (RAAS) leads to dysfunction of the vasculature, including, increased vascular tone, inflammation, fibrosis and thrombosis. Cross-talk between the main mediators of the RAAS, aldosterone and angiotensin (Ang) II, participates in the development of this vascular dysfunction. Recent studies have highlighted the molecular mechanisms supporting this cross-talk in vascular smooth muscle cells (VSMCs). Some of the signaling pathways activated by the Ang II type 1 receptor (AT(1)R) are dependent on the mineralocorticoid receptor (MR) and vice versa. VSMC signaling pathways involved in migration and growth are under the control of cross-talk between aldosterone and Ang II. A synergistic mechanism leads to potentiation of signaling pathways activated by each agent. The genomic and non-genomic mechanisms activated by aldosterone cooperate with Ang II to regulate vascular tone and gene expression of pro-inflammatory and pro-fibrotic molecules. This cross-talk is dependent on the non-receptor tyrosine kinase c-Src, and on receptor tyrosine kinases, EGFR and PDGFR, and leads to activation of MAP kinases and growth, migration and inflammatory effects. These new findings will contribute to development of better treatments for conditions in which the RAAS is excessively activated.
Steroids 2011 Aug
PMID:Cross-talk between aldosterone and angiotensin signaling in vascular smooth muscle cells. 2137 87


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