Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coactivators are required for activation of target genes by nuclear receptors. A well-studied class of coactivators, the p160 proteins, use short nuclear receptor interaction domains (NR boxes) to bind to the activated ligand-binding domain of a nuclear receptor. To investigate how selective estrogen receptor modulators (SERMs) affect NR box recruitment, we compared the recruitment of p160 NR box peptides to the estrogen receptor (ER)alpha and ER beta in the presence of 17beta-estradiol (E2), 4-OH tamoxifen (4-OH Tam), LY 117018 (a raloxifene analog), and ICI 182780 (ICI, an ER antagonist). Our coactivator interaction assay utilizes time-resolved fluorescence technology to assess the binding of the 10 NR boxes derived from the three known p160 coactivators (SRC-1, -2, -3) to the ER subtypes in the presence of each ligand. The SERMs we studied did not increase NR box binding to either ER alpha or ER beta, but instead were potent antagonists decreasing estradiol-dependent NR box binding. We also demonstrated inverse agonism for all of the SERMs tested as they dose-dependently decreased hormone-independent NR box binding to ER beta. Therefore, the SERMs studied behave as antagonists of ER alpha and ER beta NR box binding and do not increase coactivator NR box binding to either ER subtype. In addition, we examined the preference of E2-bound ER alpha and ER beta for various naturally occurring NR boxes including the 10 SRC boxes as well as the motifs from PGC-1, TRBP, TRAP220, and CBP. Interestingly, a clear preferential pattern of interaction was noted that was receptor specific.
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PMID:Effects of selective estrogen receptor modulators (SERMs) on coactivator nuclear receptor (NR) box binding to estrogen receptors. 1212 37

Summary. Insulin is known to inhibit glucose-6-phosphatase gene expression through PI 3-kinase/PKB mediated phosphorylation and inactivation of the forkhead transcription factor FKHR, which is a potent transactivator of the glucose-6-phosphatase gene. To study the function and regulation of the transcription factor FKHR in hepatic cells, we constructed a hydroxytamoxifen-inducible version of FKHR by fusing a part of the hormone binding domain of the estrogen receptor (ER) to the C-terminus of FKHR (FKHR-ER). In HepG2-cells transiently transfected with plasmids encoding the FKHR-ER fusion protein and a glucose-6-phosphatase reporter construct, hydroxytamoxifen induced a marked induction of glucose-6-phosphatase promoter activity, whereas no effect was observed in control cells. We next generated a H4IIEC3 rat hepatoma cell line stably expressing both FKHR-ER and a glucose-6-phosphatase promoter-based reporter construct. After 2h stimulation with hydroxytamoxifen, the promoter activity was stimulated 3-5 fold, and continued to increase up to 100-fold after 15 h. The response was half maximal at 0.5 microM hydroxytamoxifen. Insulin (1 nM) decreased the hydroxytamoxifen induced promoter activity by about 70% of the maximal response. This cell system can be used for (1) the identification of FKHR dependent genes and for (2) high throughput screening (HTS) of agents affecting the activity of FKHR and its regulation by insulin. Abbreviations used: FKHR, forkhead in rhabdomyosarcoma; G6Pase, glucose-6-phosphatase; PKB, protein kinase B; PI 3-kinase, phosphatidyl-inositol 3-kinase; IRU, insulin-responsive unit; Tx, 4-hydroxytamoxifen, ER, estrogen receptor; HBD, hormone binding domain
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PMID:Construction and characterization of a conditionally active construct of the insulin-regulated forkhead transcription factor FKHR. 1237 35

Flavonoids, such as daidzein and genistein, present in dietary plants like soybean, have unique chemical properties with biological activity relevant to cancer. Many flavonoids and polyphenols, including resveratrol in red wine and epigallocatechin gallate in green tea, are known antioxidants. Some of these compounds have estrogenic (and antiestrogenic) activity and are commonly referred to as phytoestrogens. A yeast-based estrogen receptor (ER) reporter assay has been used to measure the ability of flavonoids to bind to ER and activate estrogen responsive genes. Recently, estrogenic compounds were also shown to trigger rapid, nongenomic effects. The molecular mechanisms, however, have not been completely detailed and little information exists regarding their relevance to cancer progression. As a preliminary step toward elucidating rapid phytoestrogen action on breast cancer cells, we investigated the effect of 17-beta estradiol (E2), genistein, daidzein and resveratrol on the activation status of signaling proteins that regulate cell survival and invasion, the cell properties underlying breast cancer progression. The effect of these estrogenic compounds on the activation, via phosphorylation, of Akt/protein kinase B (Akt) and focal adhesion kinase (FAK) were analyzed in ER-positive and -negative human breast cancer cell lines. E2, genistein and daidzein increased whereas resveratrol decreased both Akt and FAK phosphorylation in nonmetastatic ER-positive T47D cells. In metastatic ER-negative MDA-MB-231 cells, all estrogenic compounds tested increased Akt and FAK phosphorylation. The inhibitory action of resveratrol on cell survival and proliferation is ER dependent. Therefore, all estrogenic compounds tested, including resveratrol, may exert supplementary ER-independent nongenomic effects on cell survival and migration in breast cancer cells.
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PMID:Flavonoid effects relevant to cancer. 1242 74

A member of the Forkhead transcription factor family, FKHRL1, lies downstream of the phosphatidylinositol 3-kinase-Akt activation pathway in cytokine signaling. Because the phosphatidylinositol 3-kinase-Akt activation pathway is required for BCR-ABL-mediated transformation and survival signaling in chronic myelogenous leukemia (CML), in this study we examined the involvement of FKHRL1 in the BCR-ABL-mediated signaling pathway. FKHRL1 was constitutively phosphorylated in BCR-ABL-expressing cell lines KCL22 and KU812, and its phosphorylation was inhibited by treatment with STI571, a specific inhibitor of BCR-ABL tyrosine kinase. Concomitantly, STI571 induced cell cycle arrest at the G(0)/G(1) phase, accompanied by up-regulation of a cyclin-dependent kinase inhibitor p27/Kip1 in KCL22 cells. In addition, FKHRL1 was constitutively phosphorylated in the TF-1/bcr-abl cell line ectopically expressing BCR-ABL but not in the parent TF-1 cell line. Considering several lines of evidence that phosphorylated FKHRL1 has lost transcriptional activity and that p27/Kip1 expression is positively regulated by dephosphorylated "active" FKHRL1, BCR-ABL may down-regulate p27/Kip1 expression via the loss of FKHRL1 function as a transcription factor. To demonstrate this hypothesis, we generated a tamoxifen-inducible "active FKHRL1" FKHRL1-TM (a triple mutant of FKHRL1, in which all three Akt phosphorylation sites have been mutated), estrogen receptor system in the KCL22 cell line. The addition of tamoxifen inhibited the cell growth indicating that overexpression of FKHRL1 in the nucleus antagonized deregulated proliferation of CML cells. Collectively, FKHRL1 regulates the expression of p27/Kip1 as a downstream molecule of BCR-ABL signaling in CML cells. BCR-ABL-induced loss of FKHRL1 function may be involved in oncogenic transformation of CML partially via the down-regulation of p27/Kip1 proteins.
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PMID:A member of Forkhead transcription factor FKHRL1 is a downstream effector of STI571-induced cell cycle arrest in BCR-ABL-expressing cells. 1245 69

Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.
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PMID:Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. 1255 91

Estrogen is a major sex steroid that affects the growth, maintenance, and homeostasis of the skeleton. Two isoforms of the estrogen receptor (ERalpha and ERbeta) mediate the transcriptional effects of estrogen. Although both isoforms of ER are present and functional in some human osteoblast (OB) cell lines, there is minimal information on the differential regulation of transcription by ERalpha and ERbeta homo- or heterodimers. This report demonstrates that ERalpha and ERbeta coexpression decreases the transcriptional capacity (relative to each ER isoform alone) on an estrogen response element-dependent reporter gene in OBs but not in other non-osteoblastic cell lines. These data suggest that ERalpha and ERbeta coexpression can differentially influence the degree of transcriptional activation in certain cell types. Interestingly, the overexpression of the steroid hormone receptor coactivator-1 (SRC1) resulted in preferential transcriptional enhancement by ERbeta as well as coexpressed ERalpha and ERbeta, whereas SRC2 overexpression appeared to preferentially enhance ERalpha transactivation. SRC3 overexpression failed to enhance estrogen-dependent transcription of any ER combination in OBs. Similar overexpression experiments in COS7 cells exhibited preferential enhancement of ERalpha function with all SRCs, including SRC3. Our data also demonstrated that SRC3 mRNA is reduced in osteoblastic cells, suggesting that SRC3 may have only a minor role in these cells. These data suggest that the transactivation capacity of various ER isoforms is both SRC species and cell type dependent.
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PMID:Mutual antagonism of estrogen receptors alpha and beta and their preferred interactions with steroid receptor coactivators in human osteoblastic cell lines. 1263 Sep 20

The folate receptor (FR) type alpha is a promising target for diagnostic imaging agents and therapeutic intervention in major subtypes of gynecological malignancies; however, the receptor levels in the tumors are variable and are generally relatively low in estrogen receptor (ER)-positive tumors. Here we report that the FR-alpha gene promoter is repressed in the presence of 17beta-estradiol and derepressed by the antiestrogens tamoxifen and ICI 182780 in a promoter-specific and ER-alpha-dependent manner in carcinoma cell lines including HeLa (cervical carcinoma), BG-1 (ovarian carcinoma), and IGROV-1 (ovarian carcinoma). The ligand and ER dose response of the FR-alpha promoter and its time course paralleled those of a classical estrogen response element-mediated effect. Antiestrogens produced an ER-dependent increase of up to 36-fold in the expression of the endogenous FR-alpha gene. Deletion analysis and FR-alpha/SV40 promoter chimeras showed that the ER effect is mediated exclusively within the G/C-rich region in the TATA-less P4 promoter of FR-alpha; electrophoretic mobility shift analysis demonstrated interaction of ER at only one of three G/C-rich elements. ER-beta only modestly affected FR-alpha promoter activity but did not diminish the ER-alpha-mediated effects. The ER corepressor, SMRT, enhanced the repression by 17beta-estradiol/ER, but ER coactivators, including SRC family members, did not appreciably impact the ER ligand response. The results suggest that in ER+ tumors, FR-alpha expression is directly and actively suppressed and predict that a brief treatment with antiestrogens will boost FR-alpha expression by passive derepression, enhancing the efficacy of FR-targeted diagnostic and therapeutic applications. They also reveal novel aspects of gene repression by ER.
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PMID:Modulation of the folate receptor alpha gene by the estrogen receptor: mechanism and implications in tumor targeting. 1278 87

The yeast Saccharomyces cerevisiae was used to reconstruct a human estrogen receptor alpha (ERalpha)-mediated transcription activation system. The level of reporter gene activation was dependent on both the position of the estrogen response element (ERE) relative to the translation start site and the number of EREs in the hybrid promoter. A G400V amino acid alteration in the ERalpha polypeptide decreased sensitivity to 17beta-estradiol (E(2)), demonstrating the hormone responsiveness of ERalpha to be qualitatively and quantitatively similar in yeast and mammalian cells. Coexpression of SRC-1a, a potent stimulator of ERalpha function in mammalian cells, potentiated ERalpha-mediated gene expression over fivefold in a E(2)-dependent manner. Deletion of 56 amino acids at the C-terminal end of SRC-1a resulted in a protein with enhanced ability to potentiate ERalpha-mediated gene expression, which mimics the activity of the same truncation in human SRC-1a as well as the SRC-1e isoform that has the 56 C-terminal residues replaced with a different 14 amino acid peptide. The selective estrogen receptor modulator tamoxifen acted as a weak agonist of ERalpha-mediated gene expression and this weak activity was potentiated by SRC-1. Tamoxifen had no effect on E(2)-induced gene activation in either the presence or absence of SRC-1. In contrast to previously reported yeast-based ERalpha-transactivation systems, the system reported here in which SRC-1 functions as a bona fide coactivator should permit a more thorough dissection of the factors involved in ERalpha-mediated transcriptional activation.
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PMID:Potentiation of human estrogen receptor alpha-mediated gene expression by steroid receptor coactivator-1 (SRC-1) in Saccharomyces cerevisiae. 1294 41

We have reported previously that reactivation of progesterone receptor (PR) expression in estrogen receptor (ER)- and PR-negative MDA-MB-231 breast cancer cells enabled progesterone to inhibit cell growth and invasiveness, and to induce remarkable focal adhesions. The present study addressed molecular mechanisms that mediate these anticancer effects of progesterone in the PR-transfected breast cancer cells ABC28. In response to progesterone treatment are the marked up-regulation of cyclin-dependent kinase inhibitor protein p21WAF1/CIP1 and decreased expression of cyclin A, cyclin B1, and cyclin D1 that are required for G1 progression and during cell mitosis. Progesterone also induced down-regulation of phosphorylated MAPK (p42/44 MAPK). Furthermore, this study also demonstrated that MEK inhibitor PD98059 that inhibits the phosphorylation of p42/44 MAPK also caused reduction of cyclin D1 level and inhibition of cell proliferation. These results suggest that inhibition of p42/44 MAPK pathway is part of the mechanisms mediating progesterone's growth-inhibitory effect. On the other hand, progesterone-induced focal adhesion is mediated by separate pathway. Whereas PD98059 exhibited no effects on cell adhesion, inhibitory antibody to beta1-integrin was able to reverse progesterone-induced focal adhesion and progesterone-induced increase in the phosphorylation of focal adhesion kinase. On the other hand, beta1-integrin antibody had no effect on progesterone-mediated growth inhibition and on progesterone-mediated expression of cyclins p21CIP1/WAF1 and phosphorylation of P42/P44 MAPK. In the context of complex functions of progesterone in breast cancer and reproductive organs, identification of distinct pathways offers new strategies for designing therapeutic agents to target the specific pathway so as to minimize the side effects.
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PMID:Distinct molecular pathways mediate progesterone-induced growth inhibition and focal adhesion. 1297 Jan 68

SHP-1 has been proposed to be a tumor suppressor gene for several cancers. The expression of SHP-1 protein is diminished or abolished in most leukemia and lymphoma cell lines and tissues, and in some non-hematopoietic cancer cell lines, such as estrogen receptor (ER) negative breast cancer cell lines and some colorectal cancer cell lines. However, we do not know whether the reduced SHP-1 expression is the cause of cancer diseases or the secondary effect of cancer developments. Here, we first demonstrate that SHP-1 has general tumor suppressing function in SHP-1 transfected cell lines. Transfected SHP-1 inhibits the growth of three lymphoma/leukemia cell lines (Ramos, H9, Jurkat) and one breast cancer cell line (HTB26). We also demonstrate a possible molecular mechanism for the tumor suppressing function of SHP-1: SHP-1 inhibits cell growth partly by negative regulation of activated JAK kinase. In addition, we find, for the first time, that SHP-1 down-regulates the level of TYK2 kinase in H9 cells and of JAK1 kinase in HTB26 cells, by accelerating their degradation. The SHP-1 accelerated degradation of JAK1 kinase in HTB26 cells was blocked with the treatment of MG132, a specific inhibitor for proteasome-mediated proteolysis. Our data suggest a new function of SHP-1 in the regulation of proteasome-mediated degradation pathway.
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PMID:SHP-1 suppresses cancer cell growth by promoting degradation of JAK kinases. 1462 62


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