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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article focuses on recent findings that the type V TGF-beta receptor (TbetaR-V), which co-expresses with other TGF-beta receptors (TbetaR-I, TbetaR-II, and TbetaR-III) in all normal cell types studied, is involved in growth inhibition by IGFBP-3 and TGF-beta and that TGF-beta activity is regulated by two distinct endocytic pathways (clathrin- and caveolar/lipid-raft-mediated). TGF-beta is a potent growth inhibitor for most cell types, including epithelial and endothelial cells. The signaling by which TGF-beta controls cell proliferation is not well understood. Many lines of evidence indicate that other signaling pathways, in addition to the prominent TbetaR-I/TbetaR-II/Smad2/3/4 signaling cascade, are required for mediating TGF-beta-induced growth inhibition. Recent studies revealed that TbetaR-V, which is identical to LRP-1, mediates IGF-independent growth inhibition by IGFBP-3 and mediates TGF-beta-induced growth inhibition in concert with TbetaR-I and TbetaR-II. In addition, IRS proteins and a Ser/Thr-specific protein phosphatase(s) are involved in the TbetaR-V-mediated growth inhibitory signaling cascade. The TbetaR-V signaling cascade appears to cross-talk with the TbetaR-I/TbetaR-II, insulin receptor (IR), IGF-I receptor (IGF-IR), integrin and c-Met signaling cascades. Attenuation or loss of the TbetaR-V signaling cascade may enable carcinoma cells to escape from TGF-beta growth control and may contribute to the aggressiveness and invasiveness of these cells via promoting epithelial-to-mesenchymal transdifferentiation (EMT). Finally, the ratio of TGF-beta binding to TbetaR-II and TbetaR-I is a signal controlling TGF-beta partitioning between two distinct endocytosis pathways and resultant TGF-beta responsiveness. These recent studies have provided new insights into the molecular mechanisms underlying TGF-beta-induced cellular growth inhibition, cross-talk between the TbetaR-V and other signaling cascades, the signal that controls TGF-beta responsiveness and the role of TbetaR-V in tumorigenesis.
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PMID:TGF-beta control of cell proliferation. 1608 40

Mutations of the PPP2R1B gene, which encodes the Abeta scaffolding subunit of serine/threonine protein phosphatase 2A (PP2A), have been identified in several types of cancer including lung and breast carcinoma. One of these mutations results in an alteration of glycine 90 to aspartic acid (G90D), which has been found in both tumor and genomic DNA, raising the possibility that it is associated with an increased risk for cancer. A novel microarray-based technology was used to screen for this single-nucleotide polymorphism in 387 cancer patients and 329 control individuals. These data were used for case-control and family-based comparisons in order to study the association of this polymorphism with susceptibility to lung carcinoma, breast carcinoma, and acute lymphoblastic leukemia. The frequency of the G90D polymorphism in breast cancer patients was significantly higher in cases (3%) than in controls (0.3%). The wild-type Abeta subunit interacted with the B56gamma (PPP2R5C), PR72 (PPP2R3A), and PR48 subunits of PP2A but did not interact with the B55alpha (PPP2R2A), B56alpha (PPP2R5A), or B56beta (PPP2R5B) regulatory subunits in an in vitro binding assay. The G90D alteration inhibited the interaction of Abeta with the B56gamma subunit but had no effect on binding to the PR72 subunit. These results provide evidence that the G90D alteration of the Abeta subunit of PP2A is associated with a low frequency of breast carcinoma and that the role of this alteration in transformation is likely to involve decreased interaction with the B56gamma regulatory subunit.
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PMID:The glycine 90 to aspartate alteration in the Abeta subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function. 1627 21

Cyclosporine (CSA) is a widely used immunosuppressive agent, predominantly for transplant patients. It is well recognized that transplant patients are prone to develop squamous carcinoma of the skin and mucosa, and this high incidence of squamous carcinoma in the transplant population cannot be explained by immunosuppression alone. We hypothesize that CSA may play a significant role in the transformation of normal epidermal squamous cells to carcinoma. CSA is a specific ligand for calcineurin, a ubiquitously expressed cellular serine/threonine phosphatase, that plays important roles in the immune system and cardiac muscles. Using global gene-profiling methods, we studied the short-time CSA effect on the squamous cell line (SCC-015) using Affymetrix human gene chips (Human U133, 2.0 plus chip). Multiple groups of genes were identified to be responsive to CSA treatment, including many genes of unknown functions. We then used reverse transcriptase-polymerase chain reaction and immunoblot analyses to selectively confirm the results from the chips analyses with emphasis on the regulatory molecules important for cellular functions of apoptosis, DNA damage repair, and cellular transformation. This global gene-profiling study indicated that CSA not only functions as an immunosuppressant on the immune system, but also activates/inhibits a wide array of genes important for cell-cycle regulation, apoptosis, and oncogene/tumor-suppressor activation. These functions of CSA on skin and mucosa systems at the molecular level are likely important in the pathogenesis of squamous carcinoma in transplant patients.
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PMID:Molecular basis of posttransplant squamous cell carcinoma: the potential role of cyclosporine a in carcinogenesis. 1665 84

We analyzed 12 ovarian epithelial tumors using 2D PAGE-based comparative proteomics to construct intra- and inter-tumoral distance map trees and to discover surrogate biomarkers indicative of an ovarian tumor. The analysis was performed after laser microdissection of 12 fresh-frozen tissue samples, including 4 serous, 5 mucinous, and 3 endometrioid tumors, with correlation with their histopathological characteristics. Ovarian epithelial tumors and normal tissues showed an apparent separation on the distance map tree. Mucinous carcinomas were closest to the normal group, whereas serous carcinomas were located furthest from the normal group. All mucinous tumors with aggressive histology were separated from the low malignant potential (LMP) group. The benign-looking cysts adjacent to the intraepithelial carcinoma (IEC) showed an expression pattern identical to that of the IEC area. The extent of change on the lineages leading to the mucinous and serous carcinoma was 1.98-fold different. The overall gene expression profiles of serous or endometrioid carcinomas appeared to be less affected by grade or stage than by histologic type. The potential candidate biomarkers screened in ovarian tumors and found to be significantly up-regulated in comparison to normal tissues were as follows: NM23, annexin-1, protein phosphatase-1, ferritin light chain, proteasome alpha-6, and NAGK (N-acetyl glucosamine kinase). In conclusion, ovarian mucinous tumors are distinct from other ovarian epithelial tumors. LMP mucinous tumors showing histologically aggressive features belong to mucinous carcinoma on the proteomic basis.
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PMID:Comparative proteomics of ovarian epithelial tumors. 1667 97

Fer is a nuclear and cytoplasmic intracellular tyrosine kinase. Herein we show that Fer is required for cell-cycle progression in malignant cells. Decreasing the level of Fer using the RNA interference (RNAi) approach impeded the proliferation of prostate and breast carcinoma cells and led to their arrest at the G0/G1 phase. At the molecular level, knockdown of Fer resulted in the activation of the retinoblastoma protein (pRB), and this was reflected by profound hypo-phosphorylation of pRB on both cyclin-dependent kinase CDK4 and CDK2 phosphorylation sites. Dephosphorylation of pRB was not seen upon the direct targeting of either CDK4 or CDK2 expression, and was only partially achieved by the simultaneous depletion of these two kinases. Amino-acid sequence analysis revealed two protein phosphatase 1 (PP1) binding motifs in the kinase domain of Fer and the association of Fer with the pRB phosphatase PP1alpha was verified using co-immunoprecipitation analysis. Downregulation of Fer potentiated the activation of PP1alpha and overexpression of Fer decreased the enzymatic activity of that phosphatase. Our findings portray Fer as a regulator of cell-cycle progression in malignant cells and as a potential target for cancer intervention.
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PMID:Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells. 1673 23

Cyclooxygenase-2 (Cox-2), the gastrin-release peptide (GRP) and its cognate receptor (GRP-R) are overexpressed in a significant percentage of colorectal carcinomas and are associated with cell growth, invasiveness and tumor progression. However, a molecular link between all of them in adenocarcinomas has not been established. Here, we show that bombesin (BBS), a GRP homolog, stimulates the expression of Cox-2 mRNA and protein in human colon adenocarcinoma Caco-2 cells, resulting in enhanced release of prostaglandin E(2). These effects were markedly inhibited by the specific BBS antagonist RC-3940-II. BBS promotes the activation of the nuclear factor of activated T cells (NFAT) through a Ca(2+)/calcineurin (Cn)-linked pathway. Upon BBS stimulation, the NFATc1 isoform translocates into the nucleus with a concomitant increase in NFATc1 binding to two specific recognition sites in the promoter region of the Cox-2 gene. Furthermore, inhibition of Cn activity by the immunosuppressive drug cyclosporin A impaired NFAT activation and diminished Cox-2 expression in BBS-stimulated cells. Interestingly, BBS pretreatment strongly enhances the invasive capacity of carcinoma cells, effect which was inhibited by a Cox-2-specific inhibitor. These findings provide the first evidence for the involvement of the Ca(2+)/Cn/NFAT pathway in BBS-mediated induction of genes involved in colon carcinoma invasiveness such as Cox-2.
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PMID:Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells. 1690 8

During the past three decades, allogeneic stem cell transplantation (ASCT) has developed from being an experimental therapy in patients with endstage leukemia into a well-established therapy in patients with a range of disorders of the immunohematopoietic system. Graft-versus-host disease (GVHD), acute or chronic, attacking host tissue is a major threat. However, donor immunocompetent T cells have a potent graft-versus-leukemia effect. A combination of calcineurin inhibitors and methotrexate is the standard therapy to prevent GVHD. Modulation of the immunosuppressive regimen may induce mild acute and mild chronic GVHD, reduce the risk of relapse, and improve long-term survival. Natural killer cells also play a role in this context. Killer cell immunoglobulin-like receptor incompatibility between recipient and donor may reduce the risk of relapse in patients with myeloid leukemia. Relapse of leukemia is a major cause of death after ASCT. Minimal residual disease and recipient leukemia lineage-specific chimerism are sensitive techniques for early detection of leukemic relapse. Donor lymphocyte infusions can enhance the antitumor effect, especially for patients with molecular relapse. The allogeneic graft-versus-cancer effect has been demonstrated in patients with metastatic breast, renal, colorectal, ovarian, prostatic, and pancreatic carcinoma. Mesenchymal stem cells have immunomodulatory properties and may be used for immunomodulation of GVHD and tissue repair. All things considered, the future looks promising for ASCT.
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PMID:Immunotherapy by allogeneic stem cell transplantation. 1741 40

Non-melanoma skin cancer (NMSC) affects a large proportion of renal transplant recipients, with estimates suggesting that at least half of white-skinned transplant recipients will develop NMSC following transplantation. Squamous-cell carcinoma is the most frequent NMSC following transplantation occurring at a 100-times greater risk than in the general population, while the incidence of basal cell carcinoma is increased 10-fold over the general population. The most important risk factor for the development of NMSC in renal transplant recipients is prior exposure to ultraviolet radiation, therefore, geographical location and skin type highly influence the risk of NMSC. However, both the intensity and type of immuno-suppressive therapy have been associated with an increased risk of NMSC. Given the potential anti-cancer actions of the proliferation signal inhibitors (PSIs), everolimus and sirolimus, demonstrated in both pre-clinical and clinical studies, we have analysed the effect of conversion to PSIs in 53 renal transplant recipients developing NMSC after transplantation. Remission of NMSC was observed in 37 patients and was generally well tolerated with minimal adverse events reported. Fifteen patients developed new lesions following conversion, two of these were receiving low-dose calcineurin inhibitors (CNIs) as part of their immuno-suppressive regimen suggesting that there was insufficient reduction of CNIs. PSI blood levels did not seem to affect the outcomes of conversion. These data, along with published clinical trial data suggest that conversion from CNIs to PSIs may be useful in the management of NMSC following renal transplantation.
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PMID:Use of proliferation signal inhibitors in non-melanoma skin cancer following renal transplantation. 1745 15

Cyclosporin A induces closure of the mitochondrial permeability transition pore. We aimed to investigate whether this closure results in concomitant increases in mitochondrial membrane potential (DeltaPsim) and the production of reactive oxygen species. Fluorescent probes were used to assess DeltaPsim (JC-1, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolyl-carbocyanine iodide), reactive oxygen species [DCF, 5- (and 6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester] and [Ca2+][Fluo-3, glycine N-[4-[6-[(acetyloxy)methoxy]-2,7-dichloro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-(acetyloxy)methyl ester] in human kidney cells (HK-2 cells) and in a line of human small cell carcinoma cells (GLC4 cells), because these do not express cyclosporin A-sensitive P-glycoprotein. We used transfected GLC4 cells expressing P-glycoprotein as control for GLC4 cells. NIM811 (N-methyl-4-isoleucine-cyclosporin) and PSC833 (SDZ-PSC833) were applied as selective mitochondrial permeability transition pore and P-glycoprotein blockers, respectively. To study the effect of cyclosporin A on mitochondrial function, we isolated mitochondria from fresh pig livers. Cyclosporin A and PSC833 induced a more than two-fold increase in JC-1 fluorescence in HK-2 cells, whereas NIM811 had no effect. None of the three substances induced a significant increase in JC-1 fluorescence in GLC4 cells. Despite this, cyclosporin A, NIM811 and PSC833 induced a 1.5-fold increase in DCF fluorescence (P<0.05) and a two-fold increase in Fluo-3 fluorescence (P<0.05). Studies in isolated mitochondria showed that blockage of mitochondrial permeability transition pores by cyclosporin A affected neither DeltaPsim, ATP synthesis, nor respiration rate. The mitochondrial permeability transition pore blockers cyclosporin A and NIM811, but also the non-mitochondrial permeability transition pore blocker PSC833, induced comparable degrees of reactive oxygen species production and cytosolic [Ca2+]. Neither mitochondria, effects on P-glycoprotein nor inhibition of calcineurin therefore play a role in cyclosporin A-induced oxidative stress and disturbed Ca2+ homeostasis.
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PMID:Cyclosporin A-induced oxidative stress is not the consequence of an increase in mitochondrial membrane potential. 1750 81

Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1alpha, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms.
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PMID:Meriolins, a new class of cell death inducing kinase inhibitors with enhanced selectivity for cyclin-dependent kinases. 1780 48


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