Non-genomic actions of sex steroid hormones

Steroid hormone receptors have been traditionally considered to act via the regulation of transcriptional processes, involving nuclear translocation and binding to specific response elements, and ultimately leading to regulation of gene expression. However, novel non-transcriptional mechanisms of signal transduction through steroid hormone receptors have been identified. These so-called 'non-genomic' effects do not depend on gene transcription or protein synthesis and involve steroid-induced modulation of cytoplasmic or cell membrane-bound regulatory proteins. Several relevant biological actions of steroids have been associated with this kind of signaling. Ubiquitous regulatory cascades such as mitogen-activated protein kinases, the phosphatidylinositol 3-OH kinase and tyrosine kinases are modulated through non-transcriptional mechanisms by steroid hormones. Furthermore, steroid hormone receptor modulation of cell membrane-associated molecules such as ion channels and G-protein-coupled receptors has been shown. TIssues traditionally considered as 'non-targets' for classical steroid actions are instead found to be vividly regulated by non-genomic mechanisms. To this aim, the cardiovascular and the central nervous system provide excellent examples, where steroid hormones induce rapid vasodilatation and neuronal survival via non-genomic mechanisms, leading to relevant pathophysiological consequences. The evidence collected in the past Years indicates that target cells and organs are regulated by a complex interplay of genomic and non-genomic signaling mechanisms of steroid hormones, and the integrated action of these machineries has important functional roles in a variety of pathophysiological processes. The understanding of the molecular basis of the rapid effects of steroids is therefore important, and may in the future turn out to be of relevance for clinical purposes.

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Differential Responses to Steroid Hormones in Fibroblasts From the Vocal Fold, Trachea, and Esophagus

Endocrinology ◽

10.1210/en.2014-1605 ◽

2015 ◽

Vol 156 (3) ◽

pp. 1000-1009 ◽

Cited By ~ 15

Author(s):

Shigeyuki Mukudai ◽

Ken Ichi Matsuda ◽

Takeshi Nishio ◽

Yoichiro Sugiyama ◽

Hideki Bando ◽

...

Keyword(s):

Androgen Receptor ◽

Steroid Hormones ◽

Vocal Fold ◽

Hormone Receptors ◽

Steroid Hormone ◽

Vocal Folds ◽

Steroid Hormone Receptors ◽

Male Rats ◽

Target Cells ◽

Cultured Fibroblasts

Abstract There is accumulating evidence that fibroblasts are target cells for steroids such as sex hormones and corticoids. The characteristics of fibroblasts vary among tissues and organs. Our aim in this study is to examine differences in responses to steroid hormones among fibroblasts from different cervicothoracic regions. We compared the actions of steroid hormones on cultured fibroblasts from the vocal folds, which are considered to be the primary target of steroid hormones, and the trachea and esophagus in adult male rats. Expression of steroid hormone receptors (androgen receptor, estrogen receptor α, and glucocorticoid receptor) was identified by immunofluorescence histochemistry. Androgen receptor was much more frequently expressed in fibroblasts from the vocal fold than in those from the trachea and esophagus. Cell proliferation analysis showed that administration of testosterone, estradiol, or corticosterone suppressed growth of all 3 types of fibroblasts. However, mRNA expression for extracellular matrix–associated genes, including procollagen I and III and elastin, and hyaluronic acid synthase I was elevated only by addition of testosterone to fibroblasts from the vocal fold. These results indicate that each steroid hormone exerts region-specific effects on cervicothoracic fibroblasts with different properties through binding to specific receptors.

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Ligand induced dissociation of the AR homodimer precedes AR monomer translocation to the nucleus

Scientific Reports ◽

10.1038/s41598-019-53139-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Ryota Shizu ◽

Kosuke Yokobori ◽

Lalith Perera ◽

Lee Pedersen ◽

Masahiko Negishi

Keyword(s):

Sexual Development ◽

Hormone Receptors ◽

Nuclear Translocation ◽

Steroid Hormone ◽

Binding Pocket ◽

Androgen Insensitivity Syndrome ◽

Steroid Hormone Receptors ◽

Wild Type ◽

Dimer Interface ◽

Androgen Insensitivity

Abstract The androgen receptor (AR) regulates male sexual development. We have now investigated AR homodimerization, hormone-dependent monomerization and nuclear translocation in PC-3 and COS-1 cells, by utilizing mutations associated with the androgen insensitivity syndrome: Pro767Ala, Phe765Leu, Met743Val and Trp742Arg. AR wild type (WT) was expressed as a homodimer in the cytoplasm, while none of these mutants formed homodimers. Unlike AR WT which responded to 1 nM dihydrotestosterone (DHT) to dissociate and translocate into the nucleus, AR Pro767Ala and Phe765Leu mutants remain as the monomer in the cytoplasm. In the crystal structure of the AR LBD homodimer, Pro767 and Phe765 reside closely on a loop that constitutes the dimer interface; their sidechains interact with the Pro767 of the other monomer and with the DHT molecule in the ligand-binding pocket. These observations place Phe765 at a position to facilitate DHT binding to Pro767 and lead to dissociation of the AR homodimer in the cytoplasm. This Pro-Phe Met relay may constitute a structural switch that mediates androgen signaling and is conserved in other steroid hormone receptors.

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The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells

Molecular and Cellular Biology ◽

10.1128/mcb.14.12.8356-8364.1994 ◽

1994 ◽

Vol 14 (12) ◽

pp. 8356-8364

Author(s):

D X Wen ◽

Y F Xu ◽

D E Mais ◽

M E Goldman ◽

D P McDonnell

Keyword(s):

Progesterone Receptor ◽

Signaling Pathways ◽

Transcriptional Activity ◽

Hormone Receptors ◽

Steroid Hormone ◽

Steroid Hormone Receptors ◽

Expression Level ◽

Sex Steroid ◽

Target Cells ◽

Human Progesterone Receptor

The biological response to progesterone is mediated by two distinct forms of the human progesterone receptor (hPR-A and hPR-B). In most cell contexts, hPR-B functions as a transcriptional activator of progesterone-responsive genes, whereas hPR-A functions as a transcriptional inhibitor of all steroid hormone receptors. We have created mutations within the carboxyl terminus of hPR which differentially effect the transcriptional activity of hPR-B in a cell- and promoter-specific manner. Analogous mutations, when introduced into hPR-A, have no effect on its ability to inhibit the transcriptional activity of other steroid hormone receptors. The observed differences in the structural requirements for hPR-B and hPR-A function suggest that transcriptional activation and repression by PR are mediated by two separate pathways within the cell. In support of this hypothesis, we have shown that hPR-A mediated repression of human estrogen receptor (hER) transcriptional activity is not dependent on hER expression level but depends largely on the absolute expression level of hPR-A. Thus, it appears that hPR-A inhibits hER transcriptional activity as a consequence of a noncompetitive interaction of hPR-A with either distinct cellular targets or different contact sites on the same target. We propose that hPR-A expression facilitates a ligand-dependent cross-talk among sex steroid receptor signaling pathways within the cell. It is likely, therefore, that alterations in the expression level of hPR-A or its cellular target can have profound effects on the physiological or pharmacological responses to sex steroid hormone receptor ligands.

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Characteristics of steroid hormone receptors in cultured MC3T3-E1 osteoblastic cells and effect of steroid hormones on cell proliferation

Calcified Tissue International ◽

10.1007/bf00316883 ◽

1992 ◽

Vol 51 (5) ◽

pp. 376-381 ◽

Cited By ~ 61

Author(s):

Akihiro Masuyama ◽

Yasuyoshi Ouchi ◽

Fumiyasu Sato ◽

Takyauki Hosoi ◽

Tetsuro Nakamura ◽

...

Keyword(s):

Cell Proliferation ◽

Steroid Hormones ◽

Hormone Receptors ◽

Steroid Hormone ◽

Steroid Hormone Receptors ◽

Osteoblastic Cells

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The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells.

Molecular and Cellular Biology ◽

10.1128/mcb.14.12.8356 ◽

1994 ◽

Vol 14 (12) ◽

pp. 8356-8364 ◽

Cited By ~ 224

Author(s):

D X Wen ◽

Y F Xu ◽

D E Mais ◽

M E Goldman ◽

D P McDonnell

Keyword(s):

Progesterone Receptor ◽

Signaling Pathways ◽

Transcriptional Activity ◽

Hormone Receptors ◽

Steroid Hormone ◽

Steroid Hormone Receptors ◽

Expression Level ◽

Sex Steroid ◽

Target Cells ◽

Human Progesterone Receptor

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Historical Perspectives: An abridged history of sex steroid hormone receptor action

Journal of Applied Physiology ◽

10.1152/jappl.2001.91.4.1854 ◽

2001 ◽

Vol 91 (4) ◽

pp. 1854-1859 ◽

Cited By ~ 16

Author(s):

Stacey A. Fannon ◽

Regina M. Vidaver ◽

Sherry A. Marts

Keyword(s):

Human Health ◽

Steroid Hormones ◽

Hormone Receptor ◽

Hormone Receptors ◽

Steroid Hormone ◽

Steroid Hormone Receptors ◽

Future Research ◽

Steroid Hormone Receptor ◽

Historical Perspectives ◽

Receptor Action

The field of steroid hormone action is well established, although it is barely more than four decades old. Pivotal experiments in the late 1950s and 1960s showed that hormone-binding components exist within nuclei of target tissues and that steroid hormones act by regulating gene expression, rather than directly influencing enzymatic processes. The understanding that steroid hormone receptors interact with the general transcription machinery and alter chromatin structure came in the 1970s and 1980s, and details of this mechanism continue to be elucidated. In addition, the discovery of rapid cellular responses to steroid hormones has led to the identification of putative membrane-bound steroid receptors that act without affecting gene transcription. As noted in the recent Institute of Medicine report Exploring the Biological Contributions to Human Health: Does Sex Matter?, the effects of steroid hormones and defects in steroid hormone receptor action have a profound impact on human health and disease. Future research directives include the development of potent, selective steroid receptor modulators, the elucidation of nongenomic steroid hormone effects, and further exploration of hormone-genome interactions.

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