scholarly journals Extranuclear Steroid Receptors: Nature and Actions

2007 ◽  
Vol 28 (7) ◽  
pp. 726-741 ◽  
Author(s):  
Stephen R. Hammes ◽  
Ellis R. Levin
Keyword(s):  
Steroid Hormones ◽  
Cell Fate ◽  
Cancer Biology ◽  
Steroid Receptors ◽  
Regulation Of Gene Expression ◽  
Steroid Receptor ◽  
Reproductive Organ ◽  
Structural Determinants ◽  
And Function

Rapid effects of steroid hormones result from the actions of specific receptors localized most often to the plasma membrane. Fast-acting membrane-initiated steroid signaling (MISS) 1leads to the modification of existing proteins and cell behaviors. Rapid steroid-triggered signaling through calcium, amine release, and kinase activation also impacts the regulation of gene expression by steroids, sometimes requiring integration with nuclear steroid receptor function. In this and other ways, the integration of all steroid actions in the cell coordinates outcomes such as cell fate, proliferation, differentiation, and migration. The nature of the receptors is of intense interest, and significant data suggest that extranuclear and nuclear steroid receptor pools are the same proteins. Insights regarding the structural determinants for membrane localization and function, as well as the nature of interactions with G proteins and other signaling molecules in confined areas of the membrane, have led to a fuller understanding of how steroid receptors effect rapid actions. Increasingly, the relevance of rapid signaling for the in vivo functions of steroid hormones has been established. Examples include steroid effects on reproductive organ development and function, cardiovascular responsiveness, and cancer biology. However, although great strides have been made, much remains to be understood concerning the integration of extranuclear and nuclear receptor functions to organ biology. In this review, we highlight the significant progress that has been made in these areas.

scholarly journals Steroid Receptor Coactivator 3 Regulates Synaptic Plasticity and Hippocampus-dependent Memory

2021 ◽  
Author(s):  
Hai-Long Zhang ◽  
Bing Zhao ◽  
Pin Yang ◽  
Yin-Quan Du ◽  
Wei Han ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Steroid Hormones ◽  
Hippocampal Neurons ◽  
Short Term Memory ◽  
Steroid Receptors ◽  
Long Term Potentiation ◽  
Steroid Receptor ◽  
Steroid Receptor Coactivator ◽  
Term Potentiation ◽  
And Function

AbstractSteroid hormones play important roles in brain development and function. The signaling of steroid hormones depends on the interaction between steroid receptors and their coactivators. Although the function of steroid receptor coactivators has been extensively studied in other tissues, their functions in the central nervous system are less well investigated. In this study, we addressed the function of steroid receptor coactivator 3 (SRC3) – a member of the p160 SRC protein family that is expressed predominantly in the hippocampus. While hippocampal development was not altered in Src3+/− mice, hippocampus-dependent functions such as short-term memory and spatial memory were impaired. We further demonstrated that the deficient learning and memory in Src3+/− mice was strongly associated with the impairment of long-term potentiation (LTP) at Schaffer Collateral-CA1 synapses. Mechanistic studies indicated that Src3+/− mutation altered the composition of N-methyl-D-aspartate receptor subunits in the postsynaptic densities of hippocampal neurons. Finally, we showed that SRC3 regulated synaptic plasticity and learning mainly dependent on its lysine acetyltransferase activity. Taken together, these results reveal previously unknown functions of SRC3 in the hippocampus and thus may provide insight into how steroid hormones regulate brain function.

Evaluation of effector cell fate and function by in vivo bioluminescence imaging

Methods ◽  
2003 ◽  
Vol 31 (2) ◽  
pp. 172-179 ◽  
Author(s):  
Matthias Edinger ◽  
Petra Hoffmann ◽  
Christopher H Contag ◽  
Robert S Negrin
Keyword(s):  
Cell Fate ◽  
Effector Cell ◽  
Bioluminescence Imaging ◽  
In Vivo Bioluminescence Imaging ◽  
And Function

scholarly journals In vivo single cell analysis reveals Gata2 dynamics in cells transitioning to hematopoietic fate

2017 ◽  
Vol 215 (1) ◽  
pp. 233-248 ◽  
Author(s):  
Christina Eich ◽  
Jochen Arlt ◽  
Chris S. Vink ◽  
Parham Solaimani Kartalaei ◽  
Polynikis Kaimakis ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Single Cell Analysis ◽  
Single Cells ◽  
Time Lapse ◽  
Hematopoietic Stem ◽  
And Function ◽  
In Cells

Cell fate is established through coordinated gene expression programs in individual cells. Regulatory networks that include the Gata2 transcription factor play central roles in hematopoietic fate establishment. Although Gata2 is essential to the embryonic development and function of hematopoietic stem cells that form the adult hierarchy, little is known about the in vivo expression dynamics of Gata2 in single cells. Here, we examine Gata2 expression in single aortic cells as they establish hematopoietic fate in Gata2Venus mouse embryos. Time-lapse imaging reveals rapid pulsatile level changes in Gata2 reporter expression in cells undergoing endothelial-to-hematopoietic transition. Moreover, Gata2 reporter pulsatile expression is dramatically altered in Gata2+/− aortic cells, which undergo fewer transitions and are reduced in hematopoietic potential. Our novel finding of dynamic pulsatile expression of Gata2 suggests a highly unstable genetic state in single cells concomitant with their transition to hematopoietic fate. This reinforces the notion that threshold levels of Gata2 influence fate establishment and has implications for transcription factor–related hematologic dysfunctions.

Constructing stem cell microenvironments using bioengineering approaches

2013 ◽  
Vol 45 (23) ◽  
pp. 1123-1135 ◽  
Author(s):  
David A. Brafman
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Disease Modeling ◽  
Mechanical Stimuli ◽  
Culture Methods ◽  
Stem Cell Fate ◽  
And Function

Within the adult organism, stem cells reside in defined anatomical microenvironments called niches. These architecturally diverse microenvironments serve to balance stem cell self-renewal and differentiation. Proper regulation of this balance is instrumental to tissue repair and homeostasis, and any imbalance can potentially lead to diseases such as cancer. Within each of these microenvironments, a myriad of chemical and physical stimuli interact in a complex (synergistic or antagonistic) manner to tightly regulate stem cell fate. The in vitro replication of these in vivo microenvironments will be necessary for the application of stem cells for disease modeling, drug discovery, and regenerative medicine purposes. However, traditional reductionist approaches have only led to the generation of cell culture methods that poorly recapitulate the in vivo microenvironment. To that end, novel engineering and systems biology approaches have allowed for the investigation of the biological and mechanical stimuli that govern stem cell fate. In this review, the application of these technologies for the dissection of stem cell microenvironments will be analyzed. Moreover, the use of these engineering approaches to construct in vitro stem cell microenvironments that precisely control stem cell fate and function will be reviewed. Finally, the emerging trend of using high-throughput, combinatorial methods for the stepwise engineering of stem cell microenvironments will be explored.

scholarly journals Steroid Receptor Coactivator 2 Is Critical for Progesterone-Dependent Uterine Function and Mammary Morphogenesis in the Mouse

2006 ◽  
Vol 26 (17) ◽  
pp. 6571-6583 ◽  
Author(s):  
Atish Mukherjee ◽  
Selma M. Soyal ◽  
Rodrigo Fernandez-Valdivia ◽  
Martine Gehin ◽  
Pierre Chambon ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Embryo Implantation ◽  
Steroid Receptor ◽  
Ovarian Activity ◽  
Mouse Uterus ◽  
Steroid Receptor Coactivator ◽  
Mammary Morphogenesis ◽  
Uterine Function ◽  
And Function

ABSTRACT Although the essential involvement of the progesterone receptor (PR) in female reproductive tissues is firmly established, the coregulators preferentially enlisted by PR to mediate its physiological effects have yet to be fully delineated. To further dissect the roles of members of the steroid receptor coactivator (SRC)/p160 family in PR-mediated reproductive processes in vivo, state-of-the-art cre-loxP engineering strategies were employed to generate a mouse model (PR Cre/+ SRC-2 flox/flox) in which SRC-2 function was abrogated only in cell lineages that express the PR. Fertility tests revealed that while ovarian activity was normal, PR Cre/+ SRC-2 flox/flox mouse uterine function was severely compromised. Absence of SRC-2 in PR-positive uterine cells was shown to contribute to an early block in embryo implantation, a phenotype not shared by SRC-1 or -3 knockout mice. In addition, histological and molecular analyses revealed an inability of the PR Cre/+ SRC-2 flox/flox mouse uterus to undergo the necessary cellular and molecular changes that precede complete P-induced decidual progression. Moreover, removal of SRC-1 in the PR Cre/+ SRC-2 flox/flox mouse uterus resulted in the absence of a decidual response, confirming that uterine SRC-2 and -1 cooperate in P-initiated transcriptional programs which lead to full decidualization. In the case of the mammary gland, whole-mount and histological analysis disclosed the absence of significant ductal side branching and alveologenesis in the hormone-treated PR Cre/+ SRC-2 flox/flox mammary gland, reinforcing an important role for SRC-2 in cellular proliferative changes that require PR. We conclude that SRC-2 is appropriated by PR in a subset of transcriptional cascades obligate for normal uterine and mammary morphogenesis and function.

scholarly journals Control of Steroid Receptor Dynamics and Function by Genomic Actions of the Cochaperones p23 and Bag-1L

2014 ◽  
Vol 12 (1) ◽  
pp. nrs.12005 ◽  
Author(s):  
Laura Cato ◽  
Antje Neeb ◽  
Myles Brown ◽  
Andrew C. B. Cato
Keyword(s):  
Ligand Binding ◽  
Molecular Chaperones ◽  
Steroid Receptors ◽  
Steroid Receptor ◽  
Combined Effects ◽  
Receptor Dynamics ◽  
Receptor Action ◽  
Dynamics And Function ◽  
And Function ◽  
Receptor Turnover

Molecular chaperones encompass a group of unrelated proteins that facilitate the correct assembly and disassembly of other macromolecular structures of which they themselves do not remain a part. Chaperones associate with a large and diverse set of cofactors termed cochaperones that regulate their function and specificity. Chaperones and cochaperones regulate the activity of several classes of signaling molecules, including steroid receptors. Upon binding ligand, steroid receptors interact with discrete nucleotide sequences within the nucleus to control the expression of diverse physiological and developmental genes. Molecular chaperones and cochaperones are typically known to provide the correct conformation for ligand binding by the steroid receptors. While this contribution is widely accepted, recent studies have reported that they further modulate steroid receptor action outside ligand binding. Specifically, they are thought to contribute to receptor turnover, transport of the receptor to different subcellular localizations, recycling of the receptor on chromatin and stabilization of receptor DNA binding. In addition to these combined effects with molecular chaperones, cochaperones have additional functions that are independent of molecular chaperones, some of which impact steroid receptor action. Two well-studied examples are the cochaperones p23 and Bag-1L, which have been identified as modulators of steroid receptor activity in the nucleus. Understanding details of their regulatory action will provide new therapeutic opportunities for controlling steroid receptor action independent of the widespread effects of molecular chaperones.

scholarly journals Developmental and Transcriptional Consequences of Mutations in Drosophila TAFII60

2001 ◽  
Vol 21 (20) ◽  
pp. 6808-6819 ◽  
Author(s):  
Norikazu Aoyagi ◽  
David A. Wassarman
Keyword(s):  
Rna Polymerase Ii ◽  
Cell Fate ◽  
Transcription Initiation ◽  
Developmental Regulation ◽  
Regulation Of Gene Expression ◽  
Loss Of Function ◽  
Activator Proteins ◽  
Regulate Cell Growth

ABSTRACT In vitro, the TAFII60 component of the TFIID complex contributes to RNA polymerase II transcription initiation by serving as a coactivator that interacts with specific activator proteins and possibly as a promoter selectivity factor that interacts with the downstream promoter element. In vivo roles for TAFII60 in metazoan transcription are not as clear. Here we have investigated the developmental and transcriptional requirements for TAFII60 by analyzing four independent Drosophila melanogaster TAF II 60 mutants. Loss-of-function mutations in Drosophila TAF II 60 result in lethality, indicating that TAFII60 provides a nonredundant function in vivo. Molecular analysis of TAF II 60alleles revealed that essential TAFII60 functions are provided by two evolutionarily conserved regions located in the N-terminal half of the protein. TAFII60 is required at all stages of Drosophila development, in both germ cells and somatic cells. Expression of TAFII60 from a transgene rescued the lethality of TAF II 60mutants and exposed requirements for TAFII60 during imaginal development, spermatogenesis, and oogenesis. Phenotypes of rescued TAF II 60 mutant flies implicate TAFII60 in transcriptional mechanisms that regulate cell growth and cell fate specification and suggest that TAFII60 is a limiting component of the machinery that regulates the transcription of dosage-sensitive genes. Finally, TAFII60 plays roles in developmental regulation of gene expression that are distinct from those of other TAFIIproteins.

scholarly journals Reduction of Coactivator Expression by Antisense Oligodeoxynucleotides Inhibits ERα Transcriptional Activity and MCF-7 Proliferation

2002 ◽  
Vol 16 (2) ◽  
pp. 253-270 ◽  
Author(s):  
Ilaria T. R. Cavarretta ◽  
Ratna Mukopadhyay ◽  
David M. Lonard ◽  
Lex M. Cowsert ◽  
C. Frank Bennett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Activity ◽  
Steroid Receptors ◽  
Biological Effects ◽  
Steroid Receptor ◽  
Transient Transfection ◽  
Antisense Oligodeoxynucleotides ◽  
Steroid Receptor Coactivator ◽  
Mcf 7

Abstract Steroid receptor RNA activator (SRA) is a novel coactivator for steroid receptors that acts as an RNA molecule, whereas steroid receptor coactivator (SRC) family members, such as steroid receptor coactivator-1 (SRC-1) and transcriptional intermediary factor 2 (TIF2) exert their biological effects as proteins. Individual overexpression of each of these coactivators, which can form multimeric complexes in vivo, results in stimulated ERα transcriptional activity in transient transfection assays. However there is no information on the consequences of reducing SRC-1, TIF2, or SRA expression, singly or in combination, on ERα transcriptional activity. We therefore developed antisense oligodeoxynucleotides (asODNs) to SRA, SRC-1, and TIF2 mRNAs, which rapidly and specifically reduced the expression of each of these coactivators. ERα-dependent gene expression was reduced in a dose-dependent fashion by up to 80% in cells transfected with these oligonucleotides. Furthermore, treatment of cells with combinations of SRA, SRC-1, and TIF2 asODNs reduced ERα transcriptional activity to an extent greater than individual asODN treatment alone, suggesting that these coactivators cooperate, in at least an additive fashion, to activate ERα-dependent target gene expression. Finally, treatment of MCF-7 cells with asODN against SRC-1 and TIF2 revealed a requirement of these coactivators, but not SRA, for hormone-dependent DNA synthesis and induction of estrogen-dependent pS2 gene expression, indicating that SRA and SRC family coactivators can fulfill specific functional roles. Taken together, we have developed a rapid method to reduce endogenous coactivator expression that enables an assessment of the in vivo role of specific coactivators on ERα biological action and avoids potential artifacts arising from overexpression of coactivators in transient transfection assays.

scholarly journals The stringency and magnitude of androgen-specific gene activation are combinatorial functions of receptor and nonreceptor binding site sequences.

1993 ◽  
Vol 13 (10) ◽  
pp. 6326-6335 ◽  
Author(s):  
A J Adler ◽  
A Scheller ◽  
D M Robins
Keyword(s):  
Androgen Receptor ◽  
Protein Interactions ◽  
Hormonal Regulation ◽  
Steroid Receptors ◽  
Regulation Of Gene Expression ◽  
Gene Activation ◽  
Specific Gene ◽  
Sequence Variations

The mechanism by which specific hormonal regulation of gene expression is attained in vivo is a paradox in that several of the steroid receptors recognize the same DNA element in vitro. We have characterized a complex enhancer of the mouse sex-limited protein (Slp) gene that is activated exclusively by androgens but not by glucocorticoids in transfection. Potent androgen induction requires both the consensus hormone response element (HRE) and auxiliary elements residing within the 120-bp DNA fragment C' delta 9. Multiple nonreceptor factors are involved in androgen specificity, with respect to both the elevation of androgen receptor activity and the inactivity of glucocorticoid receptor (GR), since clustered base changes at any of several sites reduce or abolish androgen induction and do not increase glucocorticoid response. However, moving the HRE as little as 10 bases away from the rest of the enhancer allows GR to function, suggesting that GR is repressed by juxtaposition to particular factors within the androgen-specific complex. Surprisingly, some sequence variations of the HRE itself, within the context of C' delta 9, alter the stringency of specificity, as well as the magnitude, of hormonal response. These HRE sequence effects on expression correspond in a qualitative manner with receptor binding, i.e., GR shows a threefold difference in affinities for HREs amongst which androgen receptor does not discriminate. Altering the HRE orientation within the enhancer also affects hormonal stringency, increasing glucocorticoid but not androgen response. The effect of these subtle variations suggests that they alter receptor position with respect to other factors. Thus, protein-protein interactions that elicit specific gene regulation are established by the array of DNA elements in a complex enhancer and can be modulated by sequence variations within these elements that may influence selection of precise protein contacts.

scholarly journals Multiple Components of the HSP90 Chaperone Complex Function in Regulation of Heat Shock Factor 1 In Vivo

1999 ◽  
Vol 19 (12) ◽  
pp. 8033-8041 ◽  
Author(s):  
Steven Bharadwaj ◽  
Adnan Ali ◽  
Nick Ovsenek
Keyword(s):  
Heat Shock ◽  
Dynamic Equilibrium ◽  
Steroid Receptors ◽  
Complex Function ◽  
Steroid Receptor ◽  
Current Evidence ◽  
Heat Shock Factor 1 ◽  
Receptor Complexes ◽  
Hsp90 Chaperone

ABSTRACT Rapid and transient activation of heat shock genes in response to stress is mediated in eukaryotes by the heat shock transcription factor HSF1. It is well established that cells maintain a dynamic equilibrium between inactive HSF1 monomers and transcriptionally active trimers, but little is known about the mechanism linking HSF1 to reception of various stress stimuli or the factors controlling oligomerization. Recent reports have revealed that HSP90 regulates key steps in the HSF1 activation-deactivation process. Here, we tested the hypothesis that components of the HSP90 chaperone machine, known to function in the folding and maturation of steroid receptors, might also participate in HSF1 regulation. Mobility supershift assays using antibodies against chaperone components demonstrate that active HSF1 trimers exist in a heterocomplex with HSP90, p23, and FKBP52. Functional in vivo experiments in Xenopus oocytes indicate that components of the HSF1 heterocomplex, as well as other components of the HSP90 cochaperone machine, are involved in regulating oligomeric transitions. Elevation of the cellular levels of cochaperones affected the time of HSF1 deactivation during recovery: attenuation was delayed by immunophilins, and accelerated by HSP90, Hsp/c70, Hip, or Hop. In immunotargeting experiments with microinjected antibodies, disruption of HSP90, Hip, Hop, p23, FKBP51, and FKBP52 delayed attenuation. In addition, HSF1 was activated under nonstress conditions after immunotargeting of HSP90 and p23, evidence that these proteins remain associated with HSF1 monomers and function in their repression in vivo. The remarkable similarity of HSF1 complex chaperones identified here (HSP90, p23, and FKBP52) and components in mature steroid receptor complexes suggests that HSF1 oligomerization is regulated by a foldosome-type mechanism similar to steroid receptor pathways. The current evidence leads us to propose a model in which HSF1, HSP90 and p23 comprise a core heterocomplex required for rapid conformational switching through interaction with a dynamic series of HSP90 subcomplexes.

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