Extraembryonic heparin-binding epidermal growth factor-like growth factor deficiency compromises placentation in mice.

Heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) is expressed in the embryo and uterus at the implantation site, stimulating trophoblast invasive activity essential for placentation. The effect of extraembryonic HBEGF deficiency on placental development was investigated by breeding mice heterozygous for the Hbegf null mutation. On gestation day 13.

Estradiol Elicits Proapoptotic and Antiproliferative Effects in Human Trophoblast Cells.

During the first trimester of pregnancy, appropriate regulation of estradiol (E2) is essential for normal placental development. Previous studies demonstrate that premature elevation in E2 concentrations can lead to abnormal placentation, but have not fully elaborated the mechanism of this effect in the first-trimester trophoblast. Our aim was to determine whether E2 elicits trophoblast cell death or inhibits proliferation.

Modulation of nuclear receptor activity by the F domain.

The F domain located at the C-terminus of proteins is one of the least conserved regions of the estrogen receptors alpha and beta, members of the nuclear hormone receptor superfamily. Indeed, many members of the superfamily lack the F domain. However, when present, removing the F domain entirely or mutating it alters transactivation, dimerization, and the responses to agonist and antagonist ligands.

The multifunctional estrogen receptor-alpha F domain.

The members of the nuclear receptor superfamily act as transcriptional regulatory factors and exhibit a multidomain structure characterized as domains A-E/F. This review focuses on a small, relatively understudied region at the extreme carboxy-terminus of the estrogen receptor (ER) alpha, the F domain. The F domain contributes to differences in the activity of ER alpha and beta subtypes; it is required for tamoxifen's agonist activity on an estrogen response element, and it modifies the receptor's interactions with coregulators including steroid receptor coactivator-1.

Reproductive factors, hormone use, estrogen receptor expression and risk of non small-cell lung cancer in women.

Purpose: Estrogen receptor (ER) expression in lung tumors suggests that estrogens may play a role in the development of lung cancer. We evaluated the role of hormone-related factors in determining risk of non-small-cell lung cancer (NSCLC) in women. We also evaluated whether risk factors were differentially associated with cytoplasmic ER-alpha and/or nuclear ER-beta expression-defined NSCLC in postmenopausal women.

Identification of regions within the F domain of the human estrogen receptor alpha that are important for modulating transactivation and protein-protein interactions.

The estrogen receptor (ER)alpha is a biologically and clinically important ligand-modulated transcription factor. The F domain of the ERalpha modulates its functions in a ligand-, promoter-, and cell-specific manner. To identify the region(s) responsible for these functions, we characterized the effects of serial truncations within the F domain.

Activation function-1 domain of estrogen receptor regulates the agonistic and antagonistic actions of tamoxifen.

The antiestrogen tamoxifen has been widely used for decades as selective estrogen receptor (ER) modulator for ERalpha-positive breast tumors. Tamoxifen significantly reduces tumor recurrence by binding to the activation function-2 (AF-2) domain of the ER. Acquired resistance to tamoxifen in breast cancer patients is a serious therapeutic problem.

Understanding the human estrogen receptor-alpha using targeted mutagenesis.

The estrogen receptor-alpha is a wonderfully complex protein important in normal biology, breast cancer, and as a target for anti-cancer agents. We are using the available structures of the hERalpha as well as secondary structure predictions to guide site-directed mutagenesis in order to test the importance of specific interactions and regions in the ligand-regulated activity of the protein. In one area of interest, we are investigating the role of the F domain in the ligand-stimulated activity of the hERalpha.

Targeted mutation of key residues at the start of helix 12 in the hERalpha ligand-binding domain identifies the role of hydrogen-bonding and hydrophobic interactions in the activity of the protein.

Estradiol (E(2)) and tamoxifen exert their effects through two members of the nuclear receptor superfamily, estrogen receptor (ER)-alpha and -beta. We want to identify the key interactions linking ligand-binding and activity of the ERalpha. Asp-351 and Leu-536 participate in hydrogen bond (Asp-351) and hydrophobic (Leu-536) interactions at the start of helix 12 in the ligand-binding domain (LBD) of the ERalpha.

From ligand structure to biological activity: modified estratrienes and their estrogenic and antiestrogenic effects in MCF-7 cells.

A variety of compounds, including the selective estrogen receptor (ER) modulators tamoxifen and raloxifene, phytoestrogens such as genistein, and xenoestrogens such as bisphenol, bind to the estrogen receptor and elicit biological responses. Structural studies have linked the altered activity of compounds such as 4-hydroxytamoxifen, raloxifene, genistein, and tetrahydrochrysene, which have substantially different structures from estradiol (E2), to differences in the positioning of the critical "helix 12" within the ligand-binding domain (LBD) of the ER-ligand complex. However, subtle permutations of the E2 molecule would also be expected to modulate the pattern of responses within a cell.

Mutation of Leu-536 in human estrogen receptor-alpha alters the coupling between ligand binding, transcription activation, and receptor conformation.

The estrogen receptor (ER), of which there are two forms, ERalpha and ERbeta, is a ligand-modulated transcription factor important in both normal biology and as a target for agents to prevent and treat breast cancer. Crystallographic studies of the ERalpha ligand-binding domain suggest that Leu-536 may be involved in hydrophobic interactions at the start of a helix, "helix 12," that is crucial in the agonist-stimulated activity of ERalpha, as well as in the ability of antagonists to block the activity of ERalpha. We found that certain mutations of Leu-536 increased the ligand-independent activity of ERalpha although greatly reducing or eliminating the agonist activity of 17beta-estradiol (E2) and 4-hydroxytamoxifen (4OHT), on an estrogen response element-driven and an AP-1-driven reporter.

Mutations targeted to a predicted helix in the extreme carboxyl-terminal region of the human estrogen receptor-alpha alter its response to estradiol and 4-hydroxytamoxifen.

The human estrogen receptor-alpha, a member of the nuclear receptor superfamily, is a ligand-regulated transcriptional modulator. Because comparatively little is known about the extreme carboxyl-terminal region of the estrogen receptor (F domain), we used secondary structure prediction to design mutations that delete the F domain (S554stop), disrupt a possible turn (G556L/G557L), and alter a predicted helix (S559A/E562A, Q565P), and we evaluated the effects of these mutations on hormone binding and transcription activation in response to estradiol and the mixed agonist/antagonist 4-hydroxytamoxifen. Mutations that deleted the F domain (S554stop) or targeted the predicted helix (S559A/E562A, Q565P) greatly reduced or eliminated the agonist activity of 4-hydroxytamoxifen.