Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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. Forty-two ligands were constructed by the addition or relocation of double bonds, hydroxyl, keto, amino, and nitro substituents throughout the estra-l,3,5(10)-triene (estratriene) ring system. In this review, we summarize the effects of subtle changes in the estratriene molecule on the ability of the receptor complex to stimulate the growth of MCF-7 cells, or affect the expression of four estrogen-regulated genes (progesterone receptor, pS2 protein, cathepsin D, and tissue plasminogen activator), as well as undergo nuclear processing and downregulate ERalpha mRNA. The affinity of these ligands for, and mechanism of their binding with, the ERalpha have been measured, along with their effect on the conformation of the ER-ERE complex. In particular, two A-ring isomers of E2, 2- and 4-hydroxyestratriene-17beta-ol, display gene selective activity within MCF-7 cells which is dependent on complex endogenous promoters, an intact AF-2 and is sensitive to the level of SRC-1. Both of these A-ring isomers function as antiestrogens. Molecular modeling of these two A-ring isomers complexed with the ER ligand-binding domain supports the idea that the conformation of the LBD is affected by subtle changes in the estratriene structure.
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PMID:From ligand structure to biological activity: modified estratrienes and their estrogenic and antiestrogenic effects in MCF-7 cells. 1521 90

Estrogen receptor-alpha (ER alpha) is a ligand-dependent transcription factor that mediates physiological responses to 17 beta-estradiol (E2). Ligand binding rapidly down-regulates ER alpha levels through proteasomal proteolysis, but the functional impact of receptor degradation on cellular responses to E2 has not been fully established. In this study, we investigated the effect of blocking the ubiquitin-proteasome pathway on ER alpha-mediated transcriptional responses. In HeLa cells transfected with ER alpha, blocking either ubiquitination or proteasomal degradation markedly increased E2-induced expression of an ER-responsive reporter. Time course studies further demonstrated that blocking ligand-induced degradation of ER alpha resulted in prolonged stimulation of ER-responsive gene transcription. In breast cancer MCF7 cells containing endogenous ER alpha, proteasome inhibition enhanced E2-induced expression of endogenous pS2 and cathepsin D. However, inhibiting the proteasome decreased expression of progesterone receptor (PR), presumably due to the heterogeneity of the PR promoter, which contains multiple regulatory elements. In addition, in endometrial cancer Ishikawa cells overexpressing steroid receptor coactivator 1, 4-hydroxytamoxifen displayed full agonist activity and stimulated ER alpha-mediated transcription without inducing receptor degradation. Collectively, these results demonstrate that proteasomal degradation is not essential for ER alpha transcriptional activity and functions to limit E2-induced transcriptional output. The results further indicate that promoter context must be considered when evaluating the relationship between ER alpha transcription and proteasome inhibition. We suggest that the transcription of a gene driven predominantly by an estrogen-responsive element, such as pS2, is a more reliable indicator of ER alpha transcription activity than a gene like PR, which contains a complex promoter requiring cooperation between ER alpha and other transcription factors.
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PMID:Inhibiting proteasomal proteolysis sustains estrogen receptor-alpha activation. 1528 35

Estrogen receptors (ERs) regulate the transcription of genes involved in breast cancer cell proliferation, invasion and metastasis. In addition to ligand concentration, phosphorylation and coactivator/corepressor levels control ER-dependent transcription. In this study, we used MCF-7 breast cancer sublines with variable levels of the steroid receptor coactivator 1 (SRC-1) to investigate the importance of coactivator levels in basal and estrogen-inducible expression of SDF-1alpha/CXCL12, cathepsin D and cMyc. Basal expression of SDF-1alpha and cMyc but not of cathepsin D was substantially lower in a MCF-7 subline lacking SRC-1 ((MCF-7/p2) compared with MCF-7 sublines expressing SRC-1 (MCF-7/p1 and LCC2). Although estrogen efficiently induced SDF-1alpha in MCF-7/p1 cells, very little induction of this gene was observed in MCF-7/p2 cells. The absence of SRC-1 had no effect on estrogen-inducible expression cMyc and cathepsin D suggesting that coactivator levels determine the expression of only a subset of estrogen-regulated genes. Introduction of SRC-1, SRC-2/TIF-2 or SRC-3/AIB1 increased basal expression of SDF-1alpha in MCF-7/p2 cells. Consistent with the role of SDF-1alpha in mediating estrogen-induced proliferation, estrogen failed to increase proliferation of MCF-7/p2 cells. In matrigel invasion assays, conditioned media from MCF-7/p1 but not MCF-7/p2 cells increased invasion of cancer cells expressing metastasis-associated genes and CXCR4, the receptor for SDF-1alpha. These results suggest that coactivators control SDF-1alpha expression, which mediates estrogen-induced proliferation and invasion through autocrine and paracrine mechanisms, respectively. These results also provide a molecular explanation for recent observations linking co-overexpression of coactivators and her2/neu with poor prognosis: coactivators increase SDF-1alpha expression whereas her2/neu stabilize CXCR4 protein.
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PMID:The p160 family coactivators regulate breast cancer cell proliferation and invasion through autocrine/paracrine activity of SDF-1alpha/CXCL12. 1591 9