Early- and late-phase estrogenic responses in the uterus have been recognized for more than 60 years, yet mechanisms involved in their regulation remain controversial. One concept is that an early events(s), occurring within the first 6 h, prepares the uterus for later (18-30 h) increase in DNA synthesis, cell proliferation and protein synthesis. An alternate view is that the late growth phase is a result of the continuous presence of a stimulus. Discussion of either concept usually makes the assumption that all of the responses are dependent upon ligand interaction with one of the two estrogen receptor isoforms (ER1 and ER2). However, increased gene expression following injection of estrogen or xenoestrogen, in mice lacking ER1, or in which all ER-activity has been suppressed by an estrogen-antagonist, ICI 182,780 (ICI), has shown this to be an oversimplification. In this regard, accumulating evidence suggests that estrogen regulates diverse but interdependent signaling pathways in uterine biology via ER- dependent and -independent manners. While our long standing hypothesis is that estrogenic certain early responses are ER-independent, late responses are ER1- dependent, and a cross-talk between the two phases is necessary for a full complement of estrogenic responses in the uterus. Our previous and preliminary observations suggest that among several such early genes, Bip and Sik-SP are induced by estradiol- 172 (E2) and kepone in the mouse uterus via ER-independent manner as a phase-I response. Moreover, we recently showed that Bip is critically necessary in mediating E2- or kepone-dependent estrogen signaling that involves ER1 functions. Our preliminary studies also indicated that E2 induces GPR30 and ERK1/2 phoshorylation without involving ER1. Furthermore, we observed that the administration of a selective inhibitor of ERK1/2 activation (SL327), 30 min prior to E2 injection abrogates early ER- independent genes, as well as uterine wet weights during the early and late responsive phases. In contrast, injection of the inhibitor 6 h after E2 injection did not alter late effects. Collectively, these results positioned us to study early and late estrogenic responses to determine molecular relationship between the phases.
Our specific aims are to elucidate: 1. Early molecular signaling by E2 or kepone involving Sik-SP, Bip and GPR30 in the uterus. 2. Functional significance of Sik-SP and GPR30 in E2- or kepone- mediated late estrogenic responses in the uterus. Studies should yield new molecular insights involving Bip, Sik-SP and GPR30 during ER1-mediated estrogen signaling. Overall, the results will help us to define relationship and a molecular cross-talk between the two-phase estrogenic responses in the uterus.

Public Health Relevance

Our specific aims are to elucidate: 1. Early molecular signaling by E2 or kepone involving Sik-SP, Bip and GPR30 in the uterus. 2. Functional significance of Sik-SP and GPR30 in E2 or kepone mediated late estrogenic responses in the uterus. Studies should yield new molecular insights involving Bip, Sik-SP and GPR30 regulation of ER1-mediated estrogen signaling. Overall, the results will help us to define the relationship and a molecular cross-talk between the two-phase estrogenic responses in the uterus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES007814-13
Application #
8272633
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Heindel, Jerrold
Project Start
1997-05-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
13
Fiscal Year
2012
Total Cost
$330,785
Indirect Cost
$110,262
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Gao, Fei; Das, Sanjoy K (2014) Epigenetic regulations through DNA methylation and hydroxymethylation: clues for early pregnancy in decidualization. Biomol Concepts 5:95-107
Chung, Daesuk; Gao, Fei; Ostmann, Alicia et al. (2012) Nucleolar Sik-similar protein (Sik-SP) is required for the maintenance of uterine estrogen signaling mechanism via ERýý. Mol Endocrinol 26:385-98
Chung, Daesuk; Das, Sanjoy K (2011) Mouse primary uterine cell coculture system revisited: ovarian hormones mimic the aspects of in vivo uterine cell proliferation. Endocrinology 152:3246-58
Gao, Fei; Ma, Xinghong; Ostmann, Alicia B et al. (2011) GPR30 activation opposes estrogen-dependent uterine growth via inhibition of stromal ERK1/2 and estrogen receptor alpha (ER?) phosphorylation signals. Endocrinology 152:1434-47
Ma, Xinghong; Gao, Fei; Rusie, Allison et al. (2011) Decidual cell polyploidization necessitates mitochondrial activity. PLoS One 6:e26774
Das, Sanjoy K (2010) Regional development of uterine decidualization: molecular signaling by Hoxa-10. Mol Reprod Dev 77:387-96
Das, Sanjoy K (2009) Cell cycle regulatory control for uterine stromal cell decidualization in implantation. Reproduction 137:889-99
Ray, Sanhita; Xu, Fuhua; Wang, Haibin et al. (2008) Cooperative control via lymphoid enhancer factor 1/T cell factor 3 and estrogen receptor-alpha for uterine gene regulation by estrogen. Mol Endocrinol 22:1125-40
Xie, Huirong; Wang, Haibin; Tranguch, Susanne et al. (2007) Maternal heparin-binding-EGF deficiency limits pregnancy success in mice. Proc Natl Acad Sci U S A 104:18315-20
Ray, Sanhita; Xu, Fuhua; Li, Ping et al. (2007) Increased level of cellular Bip critically determines estrogenic potency for a xenoestrogen kepone in the mouse uterus. Endocrinology 148:4774-85

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