Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we further investigated the mechanisms by which pseudophosphorylated prolactin (S179D PRL) inhibits the growth of human prostate cancer cells. When treated with S179D PRL for 3 days, LnCAP cells responded by increasing expression of the vitamin D receptor (VDR) and the cell cycle regulatory molecule, p21, whereas PC3 and DU145 cells did not. After 5 days of treatment, both PC3 and DU145 cells responded. Untreated LnCAP cells express the short 1b form (SF1b) of the human prolactin receptor, but DU145 and PC3 cells express only low amounts of this receptor until elevated by treatment with S179D PRL. DU145 and PC3 cells become sensitive to the negative effects of S179D PRL on cell number after induction of the SF1b. Transfection of either SF1b or SF1a into PC3 or DU145 cells made them sensitive to S179D PRL in the 3-day time frame, a finding that was not duplicated by transfection with the long form of the receptor. Treatment of LnCAP cells with S179D PRL increased long-term activation of extracellular signal-regulated kinase 1/2 (ERK1/2). This did not occur in PC3 and DU145 cells until transfection with SF1a/SF1b. Blockade of ERK signaling eliminated S179D PRL-stimulated expression of the VDR and p21 in LnCAP cells and transfected PC3 and DU145 cells. We conclude that initiation of alternative splicing to produce SF1b, and subsequent altered signaling, contribute to the growth inhibitory mechanisms of S179D PRL. This is the first indication of a role for short prolactin receptors in the regulation of cell proliferation.
 ...
PMID:S179D prolactin increases vitamin D receptor and p21 through up-regulation of short 1b prolactin receptor in human prostate cancer cells. 1610 6

Although numerous studies have implicated vitamin D in preventing prostate cancer, the underlying mechanism(s) remains unclear. Using normal human prostatic epithelial cells, we examined the role of mitogen-activated protein kinase phosphatase 5 (MKP5) in mediating cancer preventive activities of vitamin D. Up-regulation of MKP5 mRNA by 1,25-dihydroxyvitamin-D3 (1,25D) was dependent on the vitamin D receptor. We also identified a putative positive vitamin D response element within the MKP5 promoter that associated with the vitamin D receptor following 1,25D treatment. MKP5 dephosphorylates/inactivates the stress-activated protein kinase p38. Treatment of prostate cells with 1,25D inhibited p38 phosphorylation, and MKP5 small interfering RNA blocked this effect. Activation of p38 and downstream production of interleukin 6 (IL-6) are proinflammatory. Inflammation and IL-6 overexpression have been implicated in the initiation and progression of prostate cancer. 1,25D pretreatment inhibited both UV- and tumor necrosis factor alpha-stimulated IL-6 production in normal cells via p38 inhibition. Consistent with inhibition of p38, 1,25D decreased UV-stimulated IL-6 mRNA stabilization. The ability of 1,25D to up-regulate MKP5 was maintained in primary prostatic adenocarcinoma cells but was absent in metastases-derived prostate cancer cell lines. The inability of 1,25D to regulate MKP5 in the metastasis-derived cancer cells suggests there may be selective pressure to eliminate key tumor suppressor functions of vitamin D during cancer progression. These studies reveal MKP5 as a mediator of p38 inactivation and decreased IL-6 expression by 1,25D in primary prostatic cultures of normal and adenocarcinoma cells, implicating decreased prostatic inflammation as a potential mechanism for prostate cancer prevention by 1,25D.
 ...
PMID:Inhibition of p38 by vitamin D reduces interleukin-6 production in normal prostate cells via mitogen-activated protein kinase phosphatase 5: implications for prostate cancer prevention by vitamin D. 1661 80

In intestinal cells, 1alpha,25(OH)(2)-vitamin D(3) (1alpha,25(OH)(2)D(3)) regulates gene expression via the specific intracellular vitamin D receptor and induces fast non-transcriptional responses involving stimulation of transmembrane signal transduction pathways. In the present study, we analyzed, for the first time, alterations in p38 MAPK response to 1alpha,25(OH)(2)D(3) in rat enterocytes with ageing. In enterocytes from young rats, the hormone increased, in a time- and dose-dependent fashion, the phosphorylation of p38 MAPK, peaking at 3 min (+2-fold). Basal levels of p38 MAPK phosphorylation were lower in enterocytes from old rats and the hormone response was greatly diminished (+0.5-fold at 3 min). p38 MAPK phosphorylation impairment in old animals was not related to significant changes of the kinase protein expression and do not explain the decreased response to 1alpha,25(OH)(2)D(3). Extracellular and intracellular Ca(2+) chelation or c-Src pharmacological inhibition suppressed hormone activation of p38 MAPK in both, young and aged rats, demonstrating that Ca(2+) and the non-receptor tyrosine kinase c-Src are required for full activation of p38 MAPK in cells stimulated with 1alpha,25(OH)(2)D(3). Two other vitamin D(3) metabolites, 25(OH)D(3) and 24,25(OH)(2)D(3, )also enhanced p38 phosphorylation, and to a similar extent than 1alpha,25(OH)(2)D(3), an ability that is lost with ageing. Enterocyte exposure to the hormone also resulted in the rapid induction of c-fos protein (peaking at 5 min, +3-fold) and to a greater extent than that of mRNA induction. With ageing, 1alpha,25(OH)(2)D(3)-dependent increase of c-fos protein level was diminished, but c-fos mRNA expression was not different from young animals. Impairment of 1alpha,25(OH)(2)D(3) activation of p38 MAPK upon ageing and abnormal hormone regulation of the c-fos oncoprotein synthesis may affect intestinal cell function.
 ...
PMID:Age-related alteration of 1alpha,25(OH)2-vitamin D3-dependent activation of p38 MAPK in rat intestinal cells. 1685 59

Studies in our laboratory demonstrate that vitamin D (1,25 dihydroxycholecalciferol or calcitriol) has significant antitumor activity in vitro and in vivo in murine and human squamous cell, prostate, lung, pancreatic and myeloma model systems. Calcitriol induces G0/G1 arrest, modulates p27 and p21, the cyclin-dependent kinase (cdk) inhibitors implicated in G1 arrest, and induces cleavage of caspase 3, PARP and the mitogen-activated protein kinase (MEK) in a caspase-dependent manner. Calcitriol also decreases phospho-Erk (P-Erk) and phospho-Akt (P-Akt), kinases that regulate cell survival pathways and up-regulate the pro-apoptotic signaling molecule, MEKK-1. Glucocorticoids enhance calcitriol-mediated activities pre-clinically in vitro and in vivo. Dexamethasone (dex) significantly potentiated the antitumor effect of calcitriol and decreased calcitriol-induced hypercalcemia. Both in vitro and in vivo, dex increased vitamin D receptor (VDR) ligand binding in the tumor while decreasing binding in intestinal mucosa, the site of calcium absorption. These studies demonstrated that calcitriol has significant antiproliferative activity in a number of pre-clinical model systems and form the groundwork for on-going clinical studies investigating calcitriol as an anticancer agent.
 ...
PMID:The antitumor efficacy of calcitriol: preclinical studies. 1688 62

1alpha-25-Dihydroxyvitamin D3 (calcitriol), the biologically active metabolite of vitamin D, is known to regulate calcium and phosphate levels in bone metabolism. It is also known to influence proliferation and differentiation in carcinoma cells mediated by the vitamin D receptor (VDR). The antiproliferative effects of calcitriol are believed to be mediated by the nuclear pathway via binding the activated receptor to vitamin D-responsive elements. This induces the vitamin D-responsive genes. Another possible pathway might be the MAPK-cascade or rapid response pathway. The interaction of calcitriol and the MAP-kinase-cascade was evaluated on VDR-positive MCF-7 cells and VDR-negative MDA-MB-231 breast cancer cells. The cells were incubated with calcitriol solution at 10(-7) M and 10(-9) M, or ethanol as controls, for up to 48 h. The effects of calcitriol were measured by semi-quantitative Western blotting. Calcitriol stimulated the MAP-kinases ERK1 and ERK2. A biphasic activation was found for calcitriol in VDR-positive cells after incubation for 5 to 20 min and from 2 to 24 h. However, early activation of ERK1 and ERK2 was also demonstrated in VDR-negative cells. In the controls, ethanol also induced the MAPK-cascade at 5 to 10 min. Calcitriol induction was demonstrated after incubation from 2 to 24 h. In conclusion, it seems that the early induction of the MAPK-cascade was independent of the VDR. A calcitriol-induced MAPK activation was shown after 4 h, which may have been caused by activation of the nuclear receptor pathway.
 ...
PMID:Modulation of MAPK ERK1 and ERK2 in VDR-positive and -negative breast cancer cell lines. 1688 87

The present study assesses the effects of two isoflavones, genistein and glycitein, and equol - a product of intestinal bacterial metabolism of dietary isoflavones, on vitamin D receptor (VDR) expression in an intestinal HT29 cell line. Genistein and glycitein significantly upregulated the VDR transcription and translation in HT29 cells. The effect of equol was less pronounced. Treating HT29 cells transfected with a vector containing the VDR promoter next to a luciferase reporter with genistein or glycitein resulted in significant upregulation of VDR promoter activity, in a manner similar to that induced by 17beta-estradiol (E2). Again, the effect of equol was less pronounced. VDR luciferase promoter activity was upregulated most by genistein, then by glycitein and least by equol when the VDR promoter was cotransfected with estrogen receptor beta. Reporter gene and chromatin immunoprecipitation (ChIP) assays demonstrated that E2 upregulates AP-1 and Sp-1 sites present on the VDR gene. In contrast, the same assays demonstrated that the Sp-1, but not AP-1, site is induced by the phytoestrogens. Similar to E2, genistein, glycitein and the isoflavonoid metabolite equol induced higher concentrations of intracellular free calcium, an event that could provide the upstream mechanism(s) induced by E2 and phytoestrogens that initiates the signaling cascade which results in the activation of extracellular signal-regulated kinase (ERK) signaling pathways and modulation of Sp-1 sites of the VDR gene, and culminates in enhanced VDR expression.
 ...
PMID:Phytoestrogens regulate transcription and translation of vitamin D receptor in colon cancer cells. 1708 8

The molecular mechanisms underlying antiproliferative actions of the steroid 1alpha,25-dihydroxy vitamin D(3) (1,25D) in human osteosarcoma cells are known only partially. To better understand the signaling involved in 1,25D anti-tumorigenic properties in bone, we stably silenced vitamin D receptor (VDR) expression in the human osteosarcoma SaOS-2 cell line. We found that 1,25D treatment reduced cell proliferation by approximately 25% after 3 days only in SaOS-2 cells expressing native levels of VDR protein, and involved activation of MAPK/AP-1/p21(waf1) pathways. Both sustained (3 days) and transient (15min) 1,25D treatment activated JNK and ERK1/2 MAPK signaling in a nongenomic VDR-dependent manner. However, only sustained exposure to hormone led to upregulation of p21 and subsequent genomic control of the cell cycle. Specific blockade of MEK1/MEK2 cascade upstream from ERK1/2 abrogated 1,25D activation of AP-1 and p21, and subsequent antiproliferative effects, even in the presence of a nuclear VDR. We conclude that 1,25D-induced inhibition of human osteosarcoma cell proliferation occurs via sustained activation of JNK and MEK1/MEK2 pathways downstream of nongenomic VDR signaling that leads to upregulation of a c-Jun/c-Fos (AP-1) complex, which in turn modulates p21(waf1) gene expression. Our results demonstrate a cross-talk between 1,25D/VDR nongenomic and genomic signaling at the level of MAP kinase activation that leads to reduction of cell proliferation in human osteosarcoma cells.
 ...
PMID:1alpha,25-Dihydroxyvitamin D(3) antiproliferative actions involve vitamin D receptor-mediated activation of MAPK pathways and AP-1/p21(waf1) upregulation in human osteosarcoma. 1741 93

Previously, we demonstrated the pivotal role of the vitamin D receptor (VDR) in mediating the butyrate-induced differentiation in colon cancer cells. Smad 3, a downstream component of transforming growth factor-beta (TGFbeta) signaling, has been shown to act as a coactivator of VDR and to possibly regulate the vitamin D signaling pathway. In this study, we demonstrate a distinct impact of the TGFbeta/Smad 3-signaling pathway in the butyrate-mediated VDR expression and induction of differentiation. Butyrate treatment resulted in a significant induction of the phosphorylation level of Smad 3, while the combination of butyrate and a specific TGFbeta1-antibody or a TGFbeta-receptor inhibitor considerably diminished the butyrate-induced upregulation of VDR expression. Using a specific inhibitor, we were also able to demonstrate an involvement of the p38 MAPK in the increase of Smad 3 phosphorylation following butyrate treatment, thus opening the view to further elucidate possible mechanisms mediating the upregulation of VDR expression following butyrate treatment in colon cancer cells.
 ...
PMID:The TGFbeta/Smad 3-signaling pathway is involved in butyrate-mediated vitamin D receptor (VDR)-expression. 1747 13

This study was designed to provide a direct demonstration of the importance of caveolin-1 in the compartmentalization of estrogen receptor beta (ERbeta) to the membrane, thus allowing 7beta-estradiol (E2) to control vitamin D receptor (VDR) transcription and expression. Our strategy was to obtain cell lines expressing different levels of caveolin-1. To this end, we transfected human embryonic kidney 293 cells with a caveolin-1-expressing vector and obtained three cell-line variants: one expressing high amounts of caveolin-1 (clone A), one expressing low amounts of caveolin-1 (clone B), and one expressing high amounts of the nonfunctional P132L caveolin-1 mutant (clone C), and compared these with parental (wild-type, WT) cells expressing negligible levels of caveolin-1. In clone A, ERbeta colocalized to membrane preparations and E2 treatment induced significant ERK 1/2 phosphorylation and enhanced VDR expression. In clones B and C and the WT, ERbeta did not localize to membrane preparations and E2 treatment was ineffective at inducing VDR upregulation associated with ERK 1/2 phosphorylation. Luciferase reporter gene expression assays showed that the human VDR promoter is only highly responsive to E2 treatment in clone A, except in the presence of the ER-specific inhibitor ICI182 780. Cotransfection of clone A with the VDR promoter and several mutants of MAPK kinase (MEK) demonstrated that the constitutively active form of MEK significantly increases VDR promoter activation, while the catalytically inactive construct is ineffective in this regard. In clone A cells transfected with an activation protein-1 (AP-1)-luciferase construct, E2 significantly upregulated the promoter activity, while ICI182 780 completely eliminated this E2-mediated effect. Clone A cells transfected with a VDR promoter bearing a targeted mutation towards the AP-1 site showed reduced E2-mediated activation of luciferase activity. Taken together, our data confirm the importance of caveolin-1 in the association of ERbeta to the membrane caveolae, allowing ERK 1/2 phosphorylation and upregulation of VDR.
 ...
PMID:Association of estrogen receptor beta with plasma-membrane caveola components: implication in control of vitamin D receptor. 1755 31

In hypocalcaemia, elevated parathyroid hormone transitorily down-regulates the kidney vitamin D receptor, which returns to normal levels with the rise in serum extracellular calcium [Ca(2+)](e). In this study, we investigated the mechanism that underlies VDR increase in kidney in association with elevated [Ca(2+)](e). Examination of MAP kinase signals in a proximal tubule human kidney (HK-2G) epithelial cell line showed that treatment of [Ca(2+)](e) in the culture medium elevated phosphorylation of both ERK and p38 MAPKs. Blockade of p38 phosphorylation with SB203580 or SB202190 in turn abolished [Ca(2+)](e)-mediated VDR protein increase, while treatment with PD98059 and U0126, specifically blocked ERK phosphorylation, but had no effect on VDR stimulation by [Ca(2+)](e). Furthermore, SB203580 treatment potently repressed [Ca(2+)](e)-mediated activation of VDR promoter. We also demonstrate that si-RNA knock down of p38alpha completely diminished high [Ca(2+)](e)-mediated VDR induction. Direct CaSR involvement was demonstrated by using an si-RNA of CaSR that impeded [Ca(2+)](e)-mediated induction of VDR. In conclusion, a high extracellular [Ca(2+)](e) concentration in the physiological range is capable of directly increasing renal proximal VDR expression, and the induction mechanism requires activation of the CaSR and signal mediation by the p38alpha MAP kinase pathway.
 ...
PMID:Extracellular calcium-sensing receptor activation induces vitamin D receptor levels in proximal kidney HK-2G cells by a mechanism that requires phosphorylation of p38alpha MAPK. 1797 68


<< Previous 1 2 3 4 5 6 7 8 9 Next >>