scholarly journals Mammary gland development and lactation are controlled by different glucocorticoid receptor activities

2001 ◽  
pp. 519-527 ◽  
Author(s):  
HM Reichardt ◽  
K Horsch ◽  
HJ Grone ◽  
A Kolbus ◽  
H Beug ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Mammary Gland ◽  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Protein Interaction ◽  
Milk Protein ◽  
Mammary Gland Development ◽  
Protein Protein Interaction ◽  
Gland Development

OBJECTIVE: Regulation of physiological processes by glucocorticoids is achieved by binding to the glucocorticoid receptor (GR) and subsequent modulation of gene expression, either by DNA binding-dependent mechanisms or via protein-protein interaction with other transcription factors. The purpose of this study was to define the molecular mechanism of GR underlying the control of mammary gland development and lactation. DESIGN: To dissect the mechanism of GR action in the mammary gland, we used genetically modified mice carrying a DNA binding-defective GR. These mice retain the ability to regulate transcription by protein-protein interaction but fail to control gene expression by DNA binding-dependent mechanisms. Thus, they allow the study of the mode of GR action in vivo. METHODS: The development of the mammary gland and milk protein synthesis during lactation were studied using histological and biochemical methods. RESULTS: Our findings demonstrated that the lack of the DNA binding function of GR impairs the ductal development of the mammary gland in virgin females and that this can presumably be accounted for by reduced proliferation of epithelial cells. In contrast, lactating females have normally differentiated mammary glands and are fully capable of milk protein production. This is in good agreement with the demonstration that the DNA binding-defective GR is still able to interact with phosphorylated Stat5 proteins, suggesting that transcriptional regulation by protein-protein interaction forms the basis of glucocorticoid action in this process. CONCLUSIONS: The present study has demonstrated that GR plays an important role in the mammary gland and that it uses different molecular modes of action to control development and milk protein synthesis.

Normal mammary gland growth and lactation capacity in pregnant relaxin-deficient mice

2009 ◽  
Vol 21 (4) ◽  
pp. 549 ◽  
Author(s):  
Laura J. Parry ◽  
Lenka A. Vodstrcil ◽  
Anna Madden ◽  
Stephanie H. Amir ◽  
Katrina Baldwin ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Mammary Gland ◽  
Milk Protein ◽  
Mammary Gland Development ◽  
Mammary Development ◽  
Normal Mammary Gland ◽  
Pregnant Mice ◽  
Ductal Branching ◽  
Pup Mortality ◽  
Gland Development

Pups born to mice with a targeted deletion of relaxin or its receptor (Rxfp1) die within 24 h postpartum. This has been attributed, in part, to abnormal mammary gland development in relaxin-mutant mice (Rln–/–). However, mammary development is normal in relaxin receptor-mutant (Rxfp1–/–) mice. The present study aimed to verify the mammary phenotypes in late pregnant and early lactating Rln–/– mice and to test the hypothesis that relaxin is involved in milk protein synthesis. Comparisons between late pregnant and early lactating wildtype (Rln+/+) and Rln–/– mice showed no differences in lobuloalveolar structure or ductal branching in the mammary gland. Mammary explants from Rln–/– mice also expressed β-casein and α-lactalbumin in response to lactogenic hormones at a similar level to Rln+/+ mice, implying normal milk protein synthesis. Pregnant Rln–/– mice infused with relaxin for 6 days gave birth to live pups without difficulty, and 96% of pups survived beyond 7 days. This is in contrast with the 100% pup mortality in saline-treated Rln–/– mice or 3-day relaxin-treated Rln–/– mice. Pups born to relaxin-treated Rln–/– dams weighed significantly less than Rln+/+ pups but had similar growth rates as their wildtype counterparts. In summary, relaxin is not critical for mammary gland development or β-casein and α-lactalbumin expression in late pregnant mice. In addition, Rln–/– dams did not need to be treated with relaxin postpartum for the pups to survive, suggesting that relaxin has no role in the maintenance of lactation in mice.

scholarly journals The Mineralocorticoid Receptor May Compensate for the Loss of the Glucocorticoid Receptor at Specific Stages of Mammary Gland Development

2002 ◽  
Vol 16 (9) ◽  
pp. 2008-2018 ◽  
Author(s):  
Michelle Kingsley-Kallesen ◽  
Sudit S. Mukhopadhyay ◽  
Shannon L. Wyszomierski ◽  
Susan Schanler ◽  
Günther Schütz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mammary Gland ◽  
Glucocorticoid Receptor ◽  
Mineralocorticoid Receptor ◽  
Mammary Gland Development ◽  
Mrna Levels ◽  
Wild Type ◽  
Milk Protein Gene ◽  
Milk Protein Gene Expression ◽  
Gland Development

Abstract To study the role of glucocorticoid receptor (GR) at different stages of mammary gland development, mammary anlage were rescued from GR−/− mice by transplantation into the cleared fat pad of wild-type mice. In virgin mice, GR−/− outgrowths displayed abnormal ductal morphogenesis characterized by distended lumena, multiple layers of luminal epithelial cells in some regions along the ducts, and increased periductal stroma. In contrast, the loss of GR did not result in overt phenotypic changes in mammary gland development during pregnancy, lactation, and involution. Surprisingly, despite the known synergism between glucocorticoids and prolactin in the regulation of milk protein gene expression, whey acidic protein and β-casein mRNA levels were unaffected in GR−/− transplants as compared with wild-type transplants. That mineralocorticoid receptor (MR) might compensate for the loss of GR was suggested by the detection of MR in the mammary gland at d 1 of lactation. This hypothesis was tested using explant cultures derived from the GR−/− transplants in which the mineralocorticoid fludrocortisone was able to synergistically induce β-casein gene expression in the presence of prolactin and insulin. These studies suggest that MR may compensate for the absence of GR at some, but not at all stages of mammary gland development.

scholarly journals Alteration of Mammary Gland Development and Gene Expression by In Utero Exposure to Cadmium

2017 ◽  
Vol 18 (9) ◽  
pp. 1939 ◽  
Author(s):  
Daniela Parodi ◽  
Morgan Greenfield ◽  
Claire Evans ◽  
Anna Chichura ◽  
Alexandra Alpaugh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mammary Gland ◽  
Mammary Gland Development ◽  
In Utero ◽  
In Utero Exposure ◽  
Gland Development

Functional interference between the ubiquitous and constitutive octamer transcription factor 1 (OTF-1) and the glucocorticoid receptor by direct protein-protein interaction involving the homeo subdomain of OTF-1

1992 ◽  
Vol 12 (11) ◽  
pp. 4960-4969
Author(s):  
E Kutoh ◽  
P E Strömstedt ◽  
L Poellinger
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Protein Interaction ◽  
Binding Activity ◽  
Dependent Manner ◽  
Protein Protein Interaction ◽  
Dna Binding Activity ◽  
Functional Interference

The ubiquitous and constitutive octamer transcription factor OTF-1 (Oct 1) is the target of positive regulation by the potent herpes simplex virus trans-activator VP16, which forms a complex with the homeodomain of OTF-1. Here we present evidence that the glucocorticoid receptor can negatively regulate OTF-1 function by a mechanism that is independent of DNA binding. In vivo-expressed glucocorticoid receptor inhibited in a hormone-dependent manner activation of a minimal promoter construct carrying a functional octamer site. Moreover, expression of the receptor in vivo resulted in hormone-dependent repression of OTF-1-dependent DNA-binding activity in nuclear extract. In vitro, the DNA-binding activity of partially purified OTF-1 was repressed following incubation with purified glucocorticoid receptor. Cross-linking and immunoprecipitation experiments indicated that the functional interference may be due to a strong association between these two proteins in solution. Finally, preliminary evidence indicates that the homeo subdomain of OTF-1 that directs formation of a complex with VP16 may also be critical for interaction with the glucocorticoid receptor. Thus, OTF-1 is a target for both positive and negative regulation by protein-protein interaction. Moreover, the functional interference between OTF-1 and the glucocorticoid receptor represents a novel regulatory mechanism in the cross-coupling of signal transduction pathways of nuclear receptors and constitutive transcription factors.

Transcriptional interference between c-Jun and the glucocorticoid receptor: Mutual inhibition of DNA binding due to direct protein-protein interaction

Cell ◽  
1990 ◽  
Vol 62 (6) ◽  
pp. 1205-1215 ◽  
Author(s):  
Hsin-Fang Yang-Yen ◽  
Jean-Claude Chambard ◽  
Yu-Lin Sun ◽  
Tod Smeal ◽  
Thomas J. Schmidt ◽  
...  
Keyword(s):  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Protein Interaction ◽  
Transcriptional Interference ◽  
Mutual Inhibition ◽  
Protein Protein Interaction

scholarly journals Essential Role of the Homeodomain for Pituitary Homeobox 1 Activation of Mouse Gonadotropin-Releasing Hormone Receptor Gene Expression through Interactions with c-Jun and DNA

2004 ◽  
Vol 24 (14) ◽  
pp. 6127-6139 ◽  
Author(s):  
Kyeong-Hoon Jeong ◽  
William W. Chin ◽  
Ursula B. Kaiser
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Point Mutation ◽  
Protein Interaction ◽  
Hormone Receptor ◽  
Gene Promoter ◽  
Gonadotropin Releasing Hormone ◽  
Releasing Hormone ◽  
Protein Protein Interaction ◽  
Gonadotropin Releasing Hormone Receptor

ABSTRACT The gonadotropin-releasing hormone receptor (GnRHR) is expressed primarily in the gonadotropes of the anterior pituitary. Pituitary homeobox 1 (Pitx-1) has been shown to activate pituitary-specific gene expression by direct DNA binding and/or protein-protein interaction with other transcription factors. We hypothesized that Pitx-1 might also dictate tissue-specific expression of the mouse GnRHR (mGnRHR) gene in a similar manner. Pitx-1 activated the mGnRHR gene promoter, and transactivation was localized to sequences between −308 and −264. Pitx-1 bound to this region only with low affinity. This region includes an activating protein 1 (AP-1) site, which was previously shown to be important for mGnRHR gene expression. Further characterization indicated that an intact AP-1 site was required for full Pitx-1 responsiveness. Furthermore, Pitx-1 and AP-1 were synergistic in the activation of the mGnRHR gene promoter. A Pitx-1 homeodomain (HD) point mutation, which eliminated DNA binding ability, caused only a partial reduction of transactivation, whereas deletion of the HD completely prevented transactivation. Pitx-1 interacted directly with c-Jun, and the HD was sufficient for this interaction. While the point mutation in the Pitx-1 HD did not affect interaction with c-Jun, deletion of the HD eliminated the interaction. Taken together, our studies indicate that Pitx-1 can direct transactivation of the mGnRHR gene, in part by DNA binding and in part by an action of Pitx-1 as a cofactor for AP-1, augmenting AP-1 activity through a novel protein-protein interaction between c-Jun and the HD of Pitx-1.

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