scholarly journals The p160 Steroid Receptor Coactivator 2, SRC-2, Regulates Murine Endometrial Function and Regulates Progesterone-Independent and -Dependent Gene Expression

Endocrinology ◽  
2007 ◽  
Vol 148 (9) ◽  
pp. 4238-4250 ◽  
Author(s):  
Jae-Wook Jeong ◽  
Kevin Y. Lee ◽  
Sang Jun Han ◽  
Bruce J. Aronow ◽  
John P. Lydon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microarray Analysis ◽  
Steroid Receptor ◽  
Protein Signaling ◽  
Endometrial Stromal Cells ◽  
Steroid Receptor Coactivator ◽  
Ovariectomized Mice ◽  
Uterine Function ◽  
Decidual Reaction ◽  
The Impact

The role of the p160 steroid receptor coactivator 2 (SRC-2) in the regulation of uterine function and progesterone (P4) signaling was investigated by determining the expression pattern of SRC-2 in the murine uterus during pregnancy and the impact of SRC-2 ablation on uterine function and global uterine gene expression in response to progesterone. SRC-2 is expressed in the endometrial luminal and glandular epithelium from pregnancy d 0.5. SRC-2 is then expressed in the endometrial stroma on pregnancy d 2.5–3.5. Once the embryo is implanted, SRC-2 is expressed in the endometrial stromal cells in the secondary decidual zone. This compartmental expression of SRC-2 can be mimicked by treatment of ovariectomized mice with estrogen and P4. Ablation of SRC-2 in the uterus resulted in a significant reduction in the ability of the uterus to undergo a hormonally induced decidual reaction. Microarray analysis of RNA from uteri of wild-type and SRC-2−/− mice treated with vehicle or P4 showed that SRC-2 was involved in the ability of progesterone to repress specific genes. This microarray analysis also revealed that the uteri of SRC-2−/− mice showed alterations in genes involved in estrogen receptor, Wnt, and bone morphogenetic protein signaling. This analysis indicates that SRC-2 regulates uterine function by modulating the regulation of developmentally important signaling molecules and the ability of P4 to repress specific genes.

scholarly journals Attenuation of Glucocorticoid Signaling through Targeted Degradation of p300 via the 26S Proteasome Pathway

2002 ◽  
Vol 16 (12) ◽  
pp. 2819-2827 ◽  
Author(s):  
Qiao Li ◽  
Anna Su ◽  
Jihong Chen ◽  
Yvonne A. Lefebvre ◽  
Robert J. G. Haché
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Sodium Butyrate ◽  
Steroid Receptor ◽  
26S Proteasome ◽  
Regulatory Control ◽  
Specific Gene ◽  
Control Of Gene Expression ◽  
Steroid Receptor Coactivator ◽  
Proteasome Pathway

Abstract The effects of acetylation on gene expression are complex, with changes in chromatin accessibility intermingled with direct effects on transcriptional regulators. For the nuclear receptors, both positive and negative effects of acetylation on specific gene transcription have been observed. We report that p300 and steroid receptor coactivator 1 interact transiently with the glucocorticoid receptor and that the acetyltransferase activity of p300 makes an important contribution to glucocorticoid receptor-mediated transcription. Treatment of cells with the deacetylase inhibitor, sodium butyrate, inhibited steroid-induced transcription and altered the transient association of glucocorticoid receptor with p300 and steroid receptor coactivator 1. Additionally, sustained sodium butyrate treatment induced the degradation of p300 through the 26S proteasome pathway. Treatment with the proteasome inhibitor MG132 restored both the level of p300 protein and the transcriptional response to steroid over 20 h of treatment. These results reveal new levels for the regulatory control of gene expression by acetylation and suggest feedback control on p300 activity.

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 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 Pathway Analysis Hints Towards Beneficial Effects of Long-Term Vibration on Human Chondrocytes

2018 ◽  
Vol 47 (4) ◽  
pp. 1729-1741 ◽  
Author(s):  
Ronald Lützenberg ◽  
Kendrick Solano ◽  
Christoph Buken ◽  
Jayashree Sahana ◽  
Stefan Riwaldt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microarray Analysis ◽  
Human Chondrocytes ◽  
Cartilage Tissue ◽  
Tunel Staining ◽  
Human Cartilage ◽  
Rhodamine Phalloidin ◽  
The Impact

Background/Aims: Spaceflight negatively influences the function of cartilage tissue in vivo. In vitro human chondrocytes exhibit an altered gene expression of inflammation markers after a two-hour exposure to vibration. Little is known about the impact of long-term vibration on chondrocytes. Methods: Human cartilage cells were exposed for up to 24 h (VIB) on a specialised vibration platform (Vibraplex) simulating the vibration profile which occurs during parabolic flights and compared to static control conditions (CON). Afterwards, they were investigated by phase-contrast microscopy, rhodamine phalloidin staining, microarray analysis, qPCR and western blot analysis. Results: Morphological investigations revealed no changes between CON and VIB chondrocytes. F-Actin staining showed no alterations of the cytoskeleton in VIB compared with CON cells. DAPI and TUNEL staining did not identify apoptotic cells. ICAM-1 was elevated and vimentin, beta-tubulin and osteopontin proteins were significantly reduced in VIB compared to CON cells. qPCR of cytoskeletal genes, ITGB1, SOX3, SOX5, SOX9 did not reveal differential regulations. Microarray analysis detected 13 differentially expressed genes, mostly indicating unspecific stimulations. Pathway analyses demonstrated interactions of PSMD4 and CNOT7 with ICAM. Conclusions: Long-term vibration did not damage human chondrocytes in vitro. The reduction of osteopontin protein and the down-regulation of PSMD4 and TBX15 gene expression suggest that in vitro long-term vibration might even positively influence cultured chondrocytes.

scholarly journals Interleukin-13 receptor subunit alpha-2 is a target of progesterone receptor and steroid receptor coactivator-1 in the mouse uterus†

2020 ◽  
Vol 103 (4) ◽  
pp. 760-768
Author(s):  
Ryan M Marquardt ◽  
Kevin Lee ◽  
Tae Hoon Kim ◽  
Brandon Lee ◽  
Francesco J DeMayo ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Steroid Hormones ◽  
Early Pregnancy ◽  
Stromal Cells ◽  
Knockout Mice ◽  
Steroid Receptor ◽  
Receptor Subunit ◽  
Ovarian Steroid ◽  
Endometrial Stromal Cells ◽  
Steroid Receptor Coactivator

Abstract The endometrium, composed of epithelial and stromal cell compartments, is tightly regulated by the ovarian steroid hormones estrogen (E2) and progesterone (P4) during early pregnancy. Through the progesterone receptor (PGR), steroid receptor coactivators, and other transcriptional coregulators, progesterone inhibits E2-induced cell proliferation and induces the differentiation of stromal cells in a process called decidualization to promote endometrial receptivity. Although interleukin-13 receptor subunit alpha-2 (Il13ra2) is expressed in the human and mouse endometrium, its potential role in the steroid hormone regulation of the endometrium has not been thoroughly examined. In this study, we employed PGR knockout mice and steroid receptor coactivator-1 knockout mice (SRC-1−/−) to profile the expression of Il13ra2 in the murine endometrium and determine the role of these transcriptional regulators in the hormone-responsiveness of Il13ra2 expression. Furthermore, we utilized a well-established decidualization-inducing steroidogenic cocktail and a siRNA-based knockdown of IL13RA2 to determine the importance of IL13RA2 in the decidualization of primary human endometrial stromal cells. Our findings demonstrate that Il13ra2 is expressed in the subepithelial stroma of the murine endometrium in response to ovarian steroid hormones and during early pregnancy in a PGR- and SRC-1-dependent manner. Furthermore, we show that knockdown of IL13RA2 before in vitro decidualization of primary human endometrial stromal cells partially compromises the full decidualization response. We conclude that Il13ra2 is a downstream target of progesterone through PGR and SRC-1 and plays a role in mediating the stromal action of ovarian steroid hormones.

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