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)

Recent studies have provided evidence for nuclear estrogen receptor-mediated calcium transport in intestinal mucosal cells. The possibility that, in addition, estrogens directly stimulate intestinal Ca2+ fluxes through second-messenger pathways was investigated. Exposure of enterocytes isolated from female rat duodenum to low physiological levels of 17 beta-estradiol (10(-11), 10(-10) and 10(-8) M) rapidly (1-10 min) increased (50-170%) cell 45Ca2+ influx. 17 alpha-Estradiol, dihydrotestosterone and progesterone were devoid of activity, suggesting specificity of the estrogen effect. Maximum responses induced by 17 beta-estradiol (5 min at 10(-10) M) could be abolished to a great extent (84%) by pretreating the cells with verapamil (10 microM) and nitrendipine (1 microM), involving the activation of voltage-dependent Ca2+ channels in the fast increase of rat duodenal calcium uptake by the hormone. Evidence was obtained indicating that the acute estrogen stimulation of enterocyte Ca2+ influx is mediated by the cyclic AMP/PKA pathway. 17 beta-Estradiol rapidly increased cAMP content of rat duodenal cells in parallel to the changes in Ca2+ uptake. In addition, forskolin, dibutyryl cAMP and Sp-cAMPS mimicked and Rp-cAMPS suppressed the prompt 17 beta-estradiol-induced stimulation of Ca2+ influx. These results are consistent with a direct action of estrogens in the enterocyte, presumably a non-genomic one, initiated on the cell surface and resulting in rapid activation of the cAMP pathway and Ca2+ channels, which may be relevant for regulation of intestinal calcium transport.
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PMID:Acute stimulation of intestinal cell calcium influx induced by 17 beta-estradiol via the cAMP messenger system. 880 32

Transcription-modulating drugs achieve their therapeutic effects through the modulation of gene transcription. To understand how selectivity is achieved, four groups of such drugs - including immunosuppressants, estrogen analogs, the antidiabetic thiazolidinediones, and the anti-inflammatory salicylates - will be discussed. The immunosuppressants cyclosporin A and FK506, when complexed with immunophilins, inactivate the protein phosphatase calcineurin, resulting in the inhibition of interleukin-2 gene activation. Another immunosuppressant, rapamycin, binds to the same immunophilin as FK506 but inactivates a protein kinase p70(s6k). Estrogen analogs tamoxifen and rolaxifene antagonize one estrogen receptor transactivation function (AF-2) and agonize another (AF-1). They modulate expression of a wide variety of genes, including transforming growth factor-alpha, insulin-like growth factor-1, and transforming growth factor-beta3, which are important for breast and endometrial cancer proliferation and bone maintenance respectively. The antidiabetic drugs thiazolidinediones bind and activate peroxisome proliferator-activated receptor gamma and suppress insulin resistance mediated by tumor necrosis factor-alpha. Salicylates inhibit transcription factor NFkappaB, which is important for immune and inflammatory responses. Continuing understanding of molecular mechanisms of such drugs not only helps to identify better drugs for these targets but should also provide an insight into developing future transcription-modulating drugs with better selectivity and reduced toxicity.
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PMID:Transcription-modulating drugs: mechanism and selectivity. 893 43

Data obtained in our laboratory about the membrane receptor for sex steroid-binding protein (SBP-R) in human breast cancer are reported. SBP-R was detected in MCF-7 cells (estrogen receptor positive, ER+), while MDA-MB 231 cells (ER-) did not bind SBP. MCF-7 cells treated with SBP and E2 showed a marked increase of intracellular cAMP, and a significant reduction of both E2 induced cell proliferation and E2-mediated increase of progesterone receptor (PGR). The inhibition of E2 effects in MCF-7 cells was shown to be highly specific for SBP and mediated by protein kinase A, the target of cAMP. Membrane SBP-R was also evaluated in primary breast cancers. SBP-R was detectable only on ER+/PR+ samples and SBP-R+ samples presented a lower proliferation rate than negative samples. Our data, thus suggest that SBP-R and ER could be functionally related and also that SBP could modulate estrogen action at target cell site.
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PMID:Sex steroid-binding protein and its membrane receptor in estrogen-dependent breast cancer: biological and pathophysiological impact. 896 84

To determine what factors regulate gonocyte proliferation in newborn rats, we first examined the expression of several signal transduction molecules by immunocytochemistry in 3-day-old rat testis sections. We found that gonocytes specifically expressed the iota and zeta isoforms of protein kinase (PK) C (PKC) and the phosphatidylinositol 3-kinase (PI3-K). Because both the zeta PKC and PI 3-K have been shown to play a role in platelet-derived growth factor (PDGF)-induced cell proliferation, we examined the effects of PDGF on gonocytes. For this, we developed a method to obtain highly purified and viable gonocytes in culture. After enzymatic digestion, differential adhesion, and two successive gradient fractionations, the gonocyte suspension obtained was over 90% pure, as assessed by light microscopy. The viability of cultured gonocytes exceeded 90% after 48 h in the presence of 2.5% FBS used as a survival factor. Immunodetection studies showed that isolated gonocytes expressed zeta PKC, PI 3-K, and the PDGF receptor. Treatment with 10 ng/ml PDGF induced a 4-fold increase of bromodeoxyuridine incorporation into gonocytes (from 5% proliferative gonocytes under basal conditions to 20% in the presence of PDGF). Because neonatal Sertoli cells secrete high levels of the growth promoting steroid, 17 beta-estradiol, we also tested its effect and found that it induced gonocyte proliferation at a level comparable with that of PDGF and that this effect was blocked by the estrogen receptor antagonist, ICI 164384. The combination of PDGF and estradiol, however, was not additive, suggesting that their effects were mediated by common molecular target(s). These results demonstrate that PDGF and estradiol activate gonocyte proliferation in vitro, suggesting that they may act as the physiological regulators of gonocyte development in vivo.
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PMID:Regulation of rat testis gonocyte proliferation by platelet-derived growth factor and estradiol: identification of signaling mechanisms involved. 904 38

p21/Cip1/Waf1 (wild-type p53 activated fragment 1/cyclin-dependent kinase [Cdk]-interacting protein 1) is a prominent Cdk inhibitor and has been shown to be a downstream mediator of p53. In this study, we sought to clarify the clinical significance of Waf1 and the relationship between Waf1 and p53 in breast cancer. For this purpose, the expressions of Waf1 and p53 were evaluated immunohistochemically in a series of 104 patients. Waf1 was expressed in 51 (49%) of 104 tumors tested, and p53 in 33 tumors (32%). Inverse expression of these two proteins was seen in 76 cases (73%); 47 were Waf1-positive and p53-negative, and 29 were Waf1-negative and p53-positive. A comparison with clinicopathologic parameters showed that Waf1 expression correlated with negative lymph nodes (P<.01), a low histologic grade (P<.0001), and positive estrogen receptor status (P<.01). Recurrence-free survival was lower for patients with Waf1-negative tumors than for those with Waf1-positive tumors (P<.0001). In multivariate analysis, Waf1 expression and low histologic grade (1 or 2) tumors had an independent prognostic significance for recurrence-free survival. These results suggest that Waf1 is induced mainly by a p53-dependent pathway and could be a reliable indicator of recurrence in breast cancer.
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PMID:p21(Waf1/Cip1) and p53 protein expression in breast cancer. 916 66

Transient transfection experiments in which three different estrogen response element-containing reporter genes were cotransfected into HeLa cells, together with constitutively expressed estrogen receptor (ER) constructs, demonstrate that activation of the transcription of the reporter genes by epidermal growth factor (EGF) and by cholera toxin with 3-isobutyl-1-methyl-xanthine, which elevate cellular cAMP, is dependent upon the presence of functional ER. Cotransfection of the reporter genes with truncated versions of the ER shows that the two non-ligand activators of ER require different regions of the receptor to produce their effects on transcription. EGF acts primarily by means of transactivation domain AF-1, whereas cAMP acts via transactivation domain AF-2 of the ER. A point mutation that removes a major site of inducible phosphorylation within the AF-1 domain of the ER abolishes the response to EGF, but the response to estradiol and cAMP is retained. Specific inhibition of cAMP-activated protein kinase (protein kinase A) prevents the response to elevated cAMP but does not affect EGF or estradiol responses. Overexpression of the protein kinase A catalytic subunit in HeLa cells results in an amplified response to estradiol, similar to that induced by cholera toxin with 3-isobutyl-1-methyl-xanthine. Comparable experiments performed using COS-1 cells produce similar results but also reveal cell type- and promoter-specific aspects of the activation mechanisms. Apparently, the ER may be activated by three different signal molecules, estradiol, EGF, and cAMP, each using a mechanism that is distinguishable from that of the others.
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PMID:Two separate mechanisms for ligand-independent activation of the estrogen receptor. 917 52

Insulin-like growth factor-I (IGF-I) is a key factor in bone remodeling. In osteoblasts, IGF-I synthesis is enhanced by parathyroid hormone and prostaglandin E2 (PGE2) through cAMP-activated protein kinase. In rats, estrogen loss after ovariectomy leads to a rise in serum IGF-I and an increase in bone remodeling, both of which are reversed by estrogen treatment. To examine estrogen-dependent regulation of IGF-I expression at the molecular level, primary fetal rat osteoblasts were co-transfected with the estrogen receptor (hER, to ensure active ER expression), and luciferase reporter plasmids controlled by promoter 1 of the rat IGF-I gene (IGF-I P1), used exclusively in these cells. As reported, 1 microM PGE2 increased IGF-I P1 activity by 5-fold. 17beta-Estradiol alone had no effect, but dose-dependently suppressed the stimulatory effect of PGE2 by up to 90% (ED50 approximately 0.1 nM). This occurred within 3 h, persisted for at least 16 h, required ER, and appeared specific, since 17alpha-estradiol was 100-300-fold less effective. By contrast, 17beta-estradiol stimulated estrogen response element (ERE)-dependent reporter expression by up to 10-fold. 17beta-Estradiol also suppressed an IGF-I P1 construct retaining only minimal promoter sequence required for cAMP-dependent gene activation, but did not affect the 60-fold increase in cAMP induced by PGE2. There is no consensus ERE in rat IGF-I P1, suggesting novel downstream interactions in the cAMP pathway that normally enhances IGF-I expression in skeletal cells. To explore this, nuclear extract from osteoblasts expressing hER were examined by electrophoretic mobility shift assay using the atypical cAMP response element in IGF-I P1. Estrogen alone did not cause DNA-protein binding, while PGE2 induced a characteristic gel shift complex. Co-treatment with both hormones caused a gel shift greatly diminished in intensity, consistent with their combined effects on IGF-I promoter activity. Nonetheless, hER did not bind IGF-I cAMP response element or any adjacent sequences. These results provide new molecular evidence that estrogen may temper the biological effects of hormones acting through cAMP to regulate skeletal IGF-I expression and activity.
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PMID:17beta-estradiol potently suppresses cAMP-induced insulin-like growth factor-I gene activation in primary rat osteoblast cultures. 921 47

Overexpression of many growth factor receptors, as well as growth factors, has been shown to confer varying degrees of estrogen-independent growth on estrogen receptor (ER) positive breast cancer cells. The proto-oncogene Raf-1 is a key intermediate in the signal transduction pathway of many of these growth factor receptors, and when constitutively activated in fibroblasts is transforming. To examine the effects of Raf-1 kinase activity on the estrogen-dependent growth of human breast cancer cells, ER + MCF-7 breast cancer cells were stably transfected with an expression construct directing the expression of an amino-truncated protein having constitutive kinase activity. Expression of constitutively activated Raf in MCF-7 cells is incompatible with growth in the presence of estrogen; that is, cells down-regulate expression of the transfected Raf. Constitutive Raf activity does allow for growth of the cells in the absence of estrogen, suggesting that activation of growth factor signaling pathways through Raf may confer a selective advantage for growth of breast cancer cells under estrogen-deprived conditions. In addition, the high levels of Raf activity induce apoptosis in cells grown under either condition. This is a novel activity for Raf, and may occur because the levels of the constitutive Raf are extremely high in these cells.
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PMID:Constitutive Raf-1 kinase activity in breast cancer cells induces both estrogen-independent growth and apoptosis. 924 79

Rapid effects of steroid hormones have been observed in neuronal cells for many years. We show here, that in the human neuroblastoma cell line SK-N-SH, the membrane impermeable conjugated 17beta-estradiol (E2BSA) activates mitogen activated protein kinase kinase (MAPKK or MEK) and induces the phosphorylation and activation of both ERK-1 and ERK-2 (mitogen activated protein kinase or MAPK). Additionally, E2BSA induces the transcription of a reporter gene construct driven by the promoter of the mouse c-fos proto-oncogene. The effects of this membrane impermeable estrogen on c-fos transcription are not inhibited by the estrogen receptor antagonists Tamoxifen or ICI 182,780, further excluding the involvement of the intracellular estrogen receptor. This is also illustrated by the observation that E2BSA does not activate estrogen response element (ERE) mediated transcription. This is the first report of rapid membrane effects of 17beta-estradiol on growth factor related signalling pathways in neuronal cells, and indicates a potential mechanism by which 17beta-estradiol might affect the expression of genes whose promoters do not contain EREs but are responsive to factors acting through other response elements such as AP-1 and SRE sites.
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PMID:Rapid membrane effects of steroids in neuroblastoma cells: effects of estrogen on mitogen activated protein kinase signalling cascade and c-fos immediate early gene transcription. 927 96

The catalytic domains of the Raf family of protein kinases (deltaRaf) differ in their ability to activate MEK in vitro and in vivo and in their ability to oncogenically transform mammalian cells. The kinase domain of B-Raf is more active than the equivalent portion of Raf-1 which in turn is more active than A-Raf. In Raf-1 the phosphorylation or mutation to aspartic acid of two key tyrosine residues upstream of the ATP binding site has been demonstrated to significantly potentiate catalytic activity. In A-Raf the analogous amino acids are also tyrosine whereas in B-Raf they are aspartic acid. To determine if these differences in amino acid sequence influence the relative catalytic activity of the Raf kinase domains we constructed forms of deltaA-Raf, deltaB-Raf and deltaRaf-1 that encode either aspartic acid [DD], phenylalanine [FF] or tyrosine [YY] at these positions. These proteins were expressed both in mammalian cells as fusions with the hormone binding domain of the estrogen receptor and as epitope-tagged proteins in Sf9 insect cells to test their oncogenic and catalytic potentials. When expressed in Rat1 or 3T3 cells in the presence of hormone all of the deltaRaf-1:ER and deltaA-Raf:ER proteins were transforming with the exception of the [FF] form of deltaA-Raf. In general the [DD] forms of the deltaRaf-1:ER and deltaA-Raf:ER proteins were the most potently oncogenic which correlated with their ability to elicit activation of the MAP kinase pathway. Consistent with the transformation data, the catalytic activity of the [DD] forms of deltaA-Raf:ER and deltaRaf-1:ER was about ten times greater than the cognate [FF] and [YY] forms of the proteins. By contrast all of the deltaB-Raf:ER proteins were highly transforming and deltaB-Raf catalytic activity was largely unaffected by mutation of the aforementioned aspartic acids to either tyrosine or phenylalanine. Similar results were obtained with epitope-tagged forms of deltaA-Raf, deltaB-Raf and deltaRaf-1 expressed in Sf9 cells. These data provide support for the model that key tyrosine residues in the protein kinase domains of A-Raf and Raf-1 are important in the regulation of catalytic activity. In addition they demonstrate that the higher intrinsic activity of B-Raf cannot be explained simply by the presence of aspartic acids at the analogous positions.
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PMID:Mutations of critical amino acids affect the biological and biochemical properties of oncogenic A-Raf and Raf-1. 928 56


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