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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of estradiol-17beta-BSA (E(2)-BSA) on Ca(2+) uptake and its related signal pathways were examined in the primary cultured rabbit kidney proximal tubule cells. E(2)-BSA (10(-9) M) significantly stimulated Ca(2+) uptake from 2 h by 13% and at 8 h by 35% as compared to control, respectively. This stimulatory effect of E(2)-BSA was not inhibited by tamoxifen (10(-8) M, an intracellular estrogen receptor antagonist), actinomycin D (10(-7) M, a transcription inhibitor), and cycloheximide (4 x 10(-5) M, a protein synthesis inhibitor). However, E(2)-BSA-induced stimulation of Ca(2+) uptake was blocked by methoxyverapamil (10(-6) M, an L-type calcium channel blocker) and 5-(N-ethyl-N-isopropyl)-amiloride (10(-5) M, a Na(+)/H(+) antiporter blocker). These results suggest that E(2)-BSA stimulates Ca(2+) uptake through nongenomic pathways. Thus, we investigated which signal pathways were related to E(2)-BSA-induced stimulation of Ca(2+) uptake. 8-Br-cAMP (10(-6) M) alone increased Ca(2+) uptake by 22% compared to control. When E(2)-BSA combined with 8-Br-cAMP, Ca(2+) uptake was not significantly stimulated compared to E(2)-BSA. SQ 22536 (10(-6) M, an adenylate cyclase inhibitor) and myristoylated protein kinase A inhibitor amide 14-22 (10(-6) M, a protein kinase A inhibitor) blocked E(2)-BSA-induced stimulation of Ca(2+) uptake and E(2)-BSA also increased cAMP generation by 26% of that of control. In addition, TPA (0.02 ng/ml, an artificial PKC promoter) stimulated the Ca(2+) uptake by 14%, and the cotreatment of TPA and E(2)-BSA did not significantly stimulate Ca(2+) uptake compared to E(2)-BSA. E(2)-BSA-induced stimulation of Ca(2+) uptake was blocked by U 73122 (10(-6) M, a phospholipase C inhibitor) or bisindolylmaleimide I (10(-6) M, a protein kinase C inhibitor). Indeed, E(2)-BSA stimulated PKC activity by 26%. In conclusion, E(2)-BSA (10(-9) M) stimulated Ca(2+) uptake by nongenomic action, which is mediated by cAMP and PKC pathways.
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PMID:Estradiol-17beta-BSA stimulates Ca(2+) uptake through nongenomic pathways in primary rabbit kidney proximal tubule cells: involvement of cAMP and PKC. 1069 64

The intriguing biology of estrogens and progestins in their diverse target cells is determined by the structure of the hormonal ligand, the receptor subtype or isoform involved, the nature of the hormone-responsive gene promoter, and the character and balance of coactivators and corepressors that modulate the cellular response to the receptor-ligand complex. Estrogens regulate the growth, differentiation, and functioning of diverse target tissues, both within and outside of the reproductive system. Most of the actions of estrogens appear to be exerted through the estrogen receptor (ER) of target cells, an intracellular receptor that is a member of a large superfamily of proteins, which function as ligand-activated transcription factors, regulating the synthesis of specific RNAs and proteins. To understand how the ER discriminates between estrogen ligands, which activate the ER, and antiestrogen ligands, which fail to effectively activate the ER, we have generated and analyzed human ERs with mutations or other alterations in portions of the receptor. These studies provide evidence for the promoter-specific and cell-specific actions of the estrogen-occupied and antiestrogen-occupied ER, highlight a regional dissociation of the hormone-binding and transcription activation functions in domain E of the receptor, and indicate that some of the contact sites of estrogens and antiestrogens in the ER are likely different. In addition, multiple interactions among different cellular signaling pathways are involved in the regulation of gene expression and cell proliferation by the ER. In several cell types, protein kinase activators and some growth factors enhance the transcriptional activity of the ER. Cyclic AMP also alters the agonist/antagonist balance of some antiestrogens. Estrogens, and antiestrogens to a lesser extent, as well as protein kinase activators and growth factors, increase phosphorylation of the ER and possibly other proteins involved in the ER-specific response pathway, suggesting that changes in cellular phosphorylation state will be important in determining the biologic activity of the ER and the effectiveness of antiestrogens as estrogen antagonists. The ER also has important interrelationships with the progesterone receptor (PR) system in modulation of biologic responses. Liganded PR-A and PR-B can each suppress estradiol-stimulated ER activity, with the magnitude of repression dependent on the PR isoform, progestin ligand, promoter, and cell type. These findings underscore the mounting evidence for the importance of interactions between members of the steroid hormone receptor family.
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PMID:Mechanisms of action and cross-talk between estrogen receptor and progesterone receptor pathways. 1073 27

In this study, the abilities of constitutive and conditional forms of the three Raf kinases to abrogate the cytokine dependency of FDC-P1 cells were examined. The constitutively active forms (delta) of all three Raf kinases were fused to the hormone-binding domain of the estrogen receptor (ER), rendering their activities conditionally dependent upon exogenous beta-estradiol. The vast majority of deltaRaf:ER-infected FDC-P1 cells remained cytokine-dependent; however, cells were obtained at low frequency in which expression of deltaRaf:ER abrogated cytokine dependency. Isoform specific differences between the Raf kinases were observed as cytokine-independent cells were obtained more frequently from deltaA-Raf:ER than either deltaRaf-1:ER or deltaB-Raf:ER infected cells. To determine whether the regulatory phosphorylation sites in the Raf proteins were necessary for abrogation of cytokine dependency, they were changed by site-directed mutagenesis. Substitution with phenylalanine eliminated the transforming ability of the deltaB-Raf:ER and deltaRaf-1:ER kinases. However, a similar substitution in A-Raf did not extinguish its transforming activity. The activated Raf proteins induced essential downstream MEK1 activity as treatment with the MEK1 inhibitor, PD98059, suppressed Raf-mediated growth. Activated MAP kinases (ERK1 and ERK2) were detected in deltaRaf:ER-transformed cells, and their presence was dependent upon a functional MEK1 protein. The cytokine-independent phenotype required the continued activity of the deltaRaf:ER proteins as removal of beta-estradiol caused the cells to stop growing and undergo apoptosis. The Raf-responsive cells were found to express autocrine growth factors, which promoted their growth. Constitutive activation of the Raf-1 oncogene resulted in malignant transformation as cytokine-independent FDC-P1 cells infected with a retrovirus encoding an activated Raf-1 protein formed tumors upon injection of immunocompromised mice. In summary, Raf kinases can abrogate cytokine dependency, prevent apoptosis and induce the tumorigenicity of a certain subpopulation of FDC-P1 cells by a MEK1-dependent mechanism.
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PMID:Differential abilities of the Raf family of protein kinases to abrogate cytokine dependency and prevent apoptosis in murine hematopoietic cells by a MEK1-dependent mechanism. 1076 50

E2F-1 is the best known ultimate transcription factor in the cyclin/cyclin-dependent kinase/retinoblastoma gene pathway and is probably involved in carcinogenesis and tumor progression. Because E2F-1 can be detected in paraffin sections using immunohistochemical techniques, it could be a useful tumor/proliferation marker. We studied the expression of this gene product in 130 breast tissue specimens from 100 patients and compared it with the expression of Mib-1, the widely used prognostic/proliferative marker, to assess E2F-1 as a new marker of neoplastic proliferation. The percentage of E2F-1-positive cells increased from 1.9% in the normal breast (NB) to 6.3% in ductal carcinoma in situ (DCIS) and to 15.3% in invasive ductal carcinomas (IDC). In addition, higher-grade tumors as well as advanced-stage disease correlated with higher expression of E2F-1. A similar tendency of Mib-1 expression was observed. There was a positive correlation between the E2F-1 and Mib-1 indices. In an in vitro experiment, we found that a similar difference in the expression of E2F-1 existed between a nontumorigenic breast cell line and two widely used breast carcinoma cell lines. The breast carcinoma cell lines T-47D and MCF-7 had more E2F-1-positive cells than the nontumorigenic cell line MCF-10F by immunohistochemistry and Western blot analysis. Because E2F-1 expression was significantly higher in IDC and DCIS than in NB, this study indicates that deregulation of E2F-1 may be involved in the development of breast IDC. In addition, E2F-1 expression could also be involved in tumor progression because the increased E2F-1 index correlated with the known prognostic predictors of breast cancer, such as histological grade, stage, metastasis status, estrogen receptor/progesterone receptor and Mib-1 expression. Thus, E2F-1 is a promising candidate to become a new prognostic/predictive marker of breast cancer.
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PMID:E2F-1: a proliferative marker of breast neoplasia. 1079 84

It has been shown that estrogen replacement in menopausal women is effective in slowing down the progression of cognitive impairment in Alzheimer's disease. Although recent studies have demonstrated the neuroprotective effects of estrogen, the precise mechanism of neuroprotection has not been elucidated. In the present study, we show that the phosphatidylinositol 3-kinase (PI3-K) cascade is involved in the neuroprotective mechanism stimulated by estrogen. Exposure to glutamate reduced the viability of rat primary cortical neurons. Pretreatment with 10 nM 17beta-estradiol significantly attenuated the glutamate-induced toxicity. This neuroprotective effect of 17beta-estradiol was blocked by co-administration with LY294002, a selective PI3-K inhibitor, but not by co-administration with PD98059, a selective mitogen activated protein kinase kinase inhibitor. Pretreatment with ICI182780, a specific estrogen receptor antagonist, also blocked the neuroprotection. Immunoblotting assay revealed that treatment with 17beta-estradiol induced the phosphorylation of Akt/PKB, an effector immediately downstream of PI3-K. These results suggest that PI3-K mediates the neuroprotective effect of 17beta-estradiol against glutamate-induced neurotoxicity.
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PMID:Phosphatidylinositol 3-kinase mediates neuroprotection by estrogen in cultured cortical neurons. 1079 34

3,3'-Diindolylmethane (DIM), a major in vivo product of acid-catalyzed oligomerization of indole-3-carbinol (I3C), is a promising anticancer agent present in vegetables of the Brassica genus. We investigated the effects of DIM on estrogen-regulated events in human breast cancer cells and found that DIM was a promoter-specific activator of estrogen receptor (ER) function in the absence of 17beta-estradiol (E(2)). DIM weakly inhibited the E(2)-induced proliferation of ER-containing MCF-7 cells and induced proliferation of these cells in the absence of steroid, by approximately 60% of the E(2) response. DIM had little effect on proliferation of ER-deficient MDA-MB-231 cells, suggesting that it is not generally toxic at these concentrations. Although DIM did not bind to the ER in this concentration range, as shown by a competitive ER binding assay, it activated the ER to a DNA-binding species. DIM increased the level of transcripts for the endogenous pS2 gene and activated the estrogen-responsive pERE-vit-CAT and pS2-tk-CAT reporter plasmids in transiently transfected MCF-7 cells. In contrast, DIM failed to activate transcription of the simple E(2)- and diethylstilbesterol-responsive reporter construct pATC2. The estrogen antagonist ICI 182780 (7alpha-[9-[(4,4,5,5, 5-pentafluoropentyl)sulfonyl]nonyl]-estra-1,3,5(10)-triene-3, 17beta-diol) was effective against DIM-induced transcriptional activity of the pERE-vit-CAT reporter, which further supports the hypothesis that DIM is acting through the ER. We demonstrated that ligand-independent activation of the ER in MCF-7 cells could be produced following treatment with the D1 dopamine receptor agonist SKF-82958 [(+/-)6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepinehydrobromide]. We also demonstrated that the agonist effects of SKF-82958 and DIM, but not of E(2), could be blocked by co-treatment with the protein kinase A (PKA) inhibitor H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide). These results have uncovered a promoter-specific, ligand-independent activation of ER signaling for DIM that may require activation by PKA, and suggest that this major I3C product may be a selective activator of ER function.
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PMID:Ligand-independent activation of estrogen receptor function by 3, 3'-diindolylmethane in human breast cancer cells. 1082 61

The Raf oncoprotein plays critical roles in the transmission of mitogenic signals from cytokine receptors to the nucleus. There are three Raf family members: A-Raf, B-Raf and Raf-1. Conditionally active forms of the Raf proteins were created by ligating N-terminal truncated activated forms to the estrogen-receptor (ER) hormone-binding domain resulting in beta-estradiol-inducible constructs. We introduced these chimeric deltaRaf:ER oncoproteins into the murine FDC-P1 hematopoietic cell line. Two different types of cells were recovered after drug selection in medium containing either cytokine or beta-estradiol: (1) cytokine-dependent cells that expressed the deltaRaf:ER oncoproteins; and (2) Raf-responsive cells that grew in response to the deltaRaf:ER oncoprotein. Depending upon the particular deltaRaf:ER oncoprotein, cytokine-dependent cells were recovered 10(3) to 10(5) times more frequently than Raf-responsive cells. To determine whether BCL2 could synergize with the deltaRaf:ER oncoproteins and increase the frequency of cytokine-independent cells, cytokine-dependent deltaRaf:ER-expressing cells were infected with either a BCL2 containing retrovirus or an empty retroviral vector. BCL2 overexpression, by itself, did not relieve cytokine dependency of the parental cell line. However, BCL2 overexpression increased the frequency of Raf-responsive cells approximately five- to 100-fold. Cytokine-dependent deltaRaf:ER-infected cells entered the G1 phase of the cell cycle after cytokine withdrawal and entered S phase only after cytokine addition. Raf-responsive deltaRaf:ER cells entered the G1 phase of the cell cycle after estrogen deprivation and re-entered the cell cycle after addition of either IL-3 or the estrogen receptor antagonist tamoxifen which activates the deltaRaf:ER constructs. Expression of the BCL2 oncoprotein often delayed the exit from the S and G2/M phases demonstrating the protective effects BCL2 provided to these Raf and BCL2 infected cells. The deltaRaf:ER cells expressed the deltaRaf:ER proteins and downstream MEK and ERK activities after beta-estradiol treatment. Raf-responsive cells that were also infected with BCL2 expressed higher levels of BCL2 than the cells that were not infected with BCL2. Thus BCL2 can synergize with the activated Raf in the abrogation of cytokine dependency of certain hematopoietic cells. These cells will be useful in furthering our understanding of the roles of the Raf and BCL2 oncoproteins in hematopoietic cell growth, cell cycle progression and prevention of apoptosis.
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PMID:Synergy between Raf and BCL2 in abrogating the cytokine dependency of hematopoietic cells. 1086 73

c-fos is the prototypic member of a family of transcription factors that regulate many cellular processes, including proliferation. c-fos heterodimerizes with jun family members to form the AP-1 transcription factor complex which binds specific DNA recognition elements in the promoters of many genes. Following rapid induction in response to serum or growth factors, c-fos regulates expression of downstream target genes involved in cellular proliferation. Although much work has focused on activation of cell cycle regulatory genes by c-fos, less is known about negative regulation of gene expression by this transcription factor. The cyclin-dependent kinase (cdk) inhibitor p21(Cip1/WAF1) is a negative regulator of cdk activity, thereby impeding cell cycle progression. By sequence analysis, we identified a putative AP-1 element in the p21(Cip1/WAF1) promoter. To investigate how this site regulated p21(Cip1/WAF1) expression and mitigate external effects on c-fos expression, we used a c-fos/estrogen receptor (c-fosER) fusion construct in which this transcription factor is conditionally activated by estradiol. In the presence of estradiol, c-fosER downregulated p21(Cip1/WAF1) promoter activity. This inhibition was dependent on the putative AP-1 site. Activation of c-fosER induced cell cycle progression and proliferation in a manner similar to serum stimulation. We concluded that activation of c-fosER mediated transcriptional inhibition of p21(Cip1/WAF1) through a previously uncharacterized AP-1 site, revealing an important role for c-fos in negative control of cell cycle regulatory genes.
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PMID:A c-fos/Estrogen receptor fusion protein promotes cell cycle progression and proliferation of human cancer cell lines. 1089 99

Although originally synthesized as an anti-estrogen, tamoxifen (Tam) was found to be able to inhibit proliferation of estrogen receptor (ER)-negative cancer cells in vitro. However, the molecular basis of such ER-independent growth inhibition is largely unknown. We have previously demonstrated that Tam induces p21WAF1 and p27KIP1 expression in human lung cancer cells which lack ER-alpha and -beta. We found that Tam induced p21WAF1 expression via transcriptional activation. In order to determine the molecular mechanism responsible for p21WAF1 induction by Tam, we performed a deletion analysis on the p21WAF1 promoter. The minimal region in the p21WAF1 promoter required for Tam-activated induction was mapped to a contiguous stretch of 10 bp located 83 bases upstream of the transcription initiation site. Our results showed that transcription factor Sp1 and Sp3 bound to this GC-rich region and mutation of Sp1-binding sites dramatically attenuated Tam-induced p21WAF1 promoter activity. We also tried to elucidate the signaling pathway that mediated the activation of p21WAF1 by Tam. Inhibition of mitogen-activated protein kinase pathways did not block Tam-induced p21WAF1. Similarly, protein kinase C inhibitor calphostin C could not suppress Tam-induced p21WAF1. Conversely, pretreatment of a specific protein kinase A inhibitor H89 significantly attenuated the induction of p21WAF1 by Tam. Furthermore, PKA activators forskolin and dibutyryl-cAMP activated p21WAFI promoter activity and increased p21wAF1 protein level in lung cancer cells. Taken together, these results demonstrate that Tam activates the p21WAF1 promoter via Sp1-binding sites and suggest that PKA may be involved in the induction of p21wAF1 by Tam in ER-negative lung cancer cells.
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PMID:Induction of p21WAF1 expression via Sp1-binding sites by tamoxifen in estrogen receptor-negative lung cancer cells. 1094 31

To gain insight into the mechanisms involved in the cross-talk between IGF-1 receptor (IGF-1R) and estrogen receptor signaling pathways, we used MCF-7-derived cells (SX13), which exhibit a 50% reduction in IGF-1R expression. Growth of NEO cells (control MCF-7 cells) was stimulated by both IGF-1 and estradiol (E2), and the addition of both mitogens resulted in a synergistic response. Estrogen enhanced IGF-1R signaling in NEO cells, but this effect was markedly diminished in SX13 cells. Estrogen was also able to potentiate the IGF-1 effect on the expression of cyclin D1 and cyclin E and on the phosphorylation of retinoblastoma protein in control but not in SX13 cells. IGF-1 increased the protein level of p21 and the luciferase activity of the p21 promoter, whereas it only reduced the protein level of p27 without affecting p27 promoter activity. Estrogen did not affect the p21 inhibitor, but it decreased the protein level of p27 and the p27 promoter luciferase activity. These effects of both mitogens were also observed at the level of association of both cyclin-dependent kinase inhibitors with CDK2 suggesting that IGF-1 and E2 affect the activity of both p21 and p27. Taken together, these data suggest that in MCF-7 cells, estrogen potentiates the IGF-1 effect on IGF-1R signaling as well as on the cell cycle components. Moreover, IGF-1 and E2 regulate the expression of p21 and p27 and their association with CDK2 differently.
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PMID:The potentiation of estrogen on insulin-like growth factor I action in MCF-7 human breast cancer cells includes cell cycle components. 1096 23


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