Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies assessed if the serine/threonine protein phosphatase-2A (PP-2A) maintains cytoskeletal integrity of normal keratinocytes and if this differs in malignant cells. Murine and human keratinocyte cell lines contained more PP-2A activity than did the murine SCC VII/SF squamous cell carcinoma cells or primary cultures of human head and neck squamous cell carcinoma (HNSCC) cells. Since tyrosine phosphorylation of the focal adhesion proteins paxillin and FAK is indicative of more stable focal adhesions, cells were immunostained for phosphotyrosine plus either paxillin or FAK, and then examined by confocal microscopy. In non-malignant keratinocytes, phosphotyrosine staining co-localized with paxillin and FAK. This co-localization occurred at the cell periphery in a pattern resembling focal adhesions. In contrast, the co-localization of phosphotyrosine with either paxillin or FAK along the cell periphery was almost absent in the SCC cells or in keratinocytes that were treated with okadaic acid to inhibit PP-2A activity. Consistent with this was a rounded cellular morphology with less extended processes as compared to control keratinocytes. These studies indicate PP-2A maintains the organization and tyrosine-phosphorylated state of the focal adhesion proteins FAK and paxillin, and that the loss of PP-2A activity results in a loss of cytoskeletal organization, as is seen in SCC.
Clin Exp Metastasis 2004
PMID:Protein phosphatase-2A maintains focal adhesion complexes in keratinocytes and the loss of this regulation in squamous cell carcinomas. 1555 94

Patients with prostate cancer develop osteoblastic metastases when tumor cells arrive in the bone and stimulate osteoblasts by secreting growth-promoting factors. Endothelin 1 (ET-1) is believed to be a key factor in promoting osteoblastic metastasis. Selective blockade of the ET(A) receptor is an established strategy in the development of cancer therapeutics. However, the molecular mechanisms whereby prostate cancer promotes abnormal bone growth are not fully understood. In this study, we have applied genomic approaches to elucidate the molecular mechanism of stimulation of osteoblasts by ET-1. To examine the ET-1 axis, we generated genomic signatures for osteoblasts treated with ET-1, in the presence and absence of a selective ET(A) antagonist (ABT-627). The ET-1 signature was comprised of several motifs, such as osteoblastic differentiation, invasion, and suppression of apoptosis. The signature also pointed at possible activation of the calcineurin/NFAT pathway. We showed that ET-1 activates calcineurin and causes nuclear translocation of NFATc1, implicating the pathway in the ET-1-mediated stimulation of osteoblasts. We also showed that ET-1 inhibits apoptosis in osteoblasts, implying that the suppression of apoptosis may be an important factor in the promotion of osteoblastic growth by ET-1.
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PMID:Endothelin signaling in osteoblasts: global genome view and implication of the calcineurin/NFAT pathway. 1723 84

Patients with premalignant oral lesions have varying levels of risk of developing oral squamous cell carcinoma (OSCC), whose aggressiveness requires increased motility. Not known is if and how premalignant oral lesion cells acquire the increased motility characteristic of OSCC. This was addressed by immunohistochemical analysis of banked premalignant lesion tissues and by functional analyses using cultures established from premalignant oral lesions and OSCC. These studies showed premalignant oral lesion cells and OSCC to be more motile than normal keratinocytes. Concomitantly, levels of ceramide were reduced. The activity of the protein phosphatase PP-2A, which restricts motility and which can be activated by ceramide, was also diminished. This was due to IL-10 released from premalignant lesion cells. Treatment with a membrane-permeable ceramide restored PP-2A activity and blocked migration. These studies show an autocrine motility-stimulatory pathway that is mediated in premalignant lesion cells by IL-10 through its reduction of ceramide levels and inhibition of PP-2A activity.
Clin Exp Metastasis 2007
PMID:Autocrine motility-stimulatory pathways of oral premalignant lesion cells. 1737 39

The SV40 early region protein, SV40 small t antigen, promotes cell transformation through negative regulation of the protein phosphatase 2A (PP2A) family of serine-threonine phosphatases. More recently, reduced levels of PP2A activity have been found in different types of human cancer. This occurs either through inactivating mutations of PP2A structural subunits, or by upregulation of the cellular PP2A inhibitors, CIP2A and SET. Several distinct PP2A complexes have been identified that contribute directly to tumor suppression by regulating specific phosphorylation events. These studies provide us with new insights into the role of protein phosphatases in cancer initiation and maintenance.
Cancer Metastasis Rev 2008 Jun
PMID:SV40 small T antigen and PP2A phosphatase in cell transformation. 1821 40

Loss or inhibition of the serine/threonine protein phosphatase 2A (PP2A) has revealed a critical tumor suppressor function for PP2A. However, PP2A has also been shown to have important roles in cell cycle progression and survival. Therefore, PP2A is not a typical tumor suppressor. This is most likely due to the fact that PP2A represents a large number of different holoenzymes. Further understanding of PP2A function(s), and especially its tumor suppressor activity, will depend largely on our ability to determine specific targets for these different PP2A holoenzymes and to gain an understanding of how these targets confer tumor suppressor activity or contribute to cell cycle progression and cell survival. Recent work has identified c-Myc as a target of the PP2A holoenzyme, PP2A-B56alpha. This holoenzyme also negatively regulates beta-catenin expression and modulates the anti-apoptotic activity of Bcl2, thus characterizing PP2A-B56alpha as a tumor suppressor PP2A holoenzyme. This review will focus on the role of PP2A-B56alpha in regulating c-Myc and will place this tumor suppressor activity of PP2A within the context of its other tumor suppressor functions. Finally, the mechanism(s) through which PP2A-B56alpha tumor suppressor activity may be lost in cancer will be discussed.
Cancer Metastasis Rev 2008 Jun
PMID:A tumor suppressor role for PP2A-B56alpha through negative regulation of c-Myc and other key oncoproteins. 1824 11

Although the aberrant actions of protein kinases have long been known to contribute to tumor promotion and carcinogenesis, roles for protein phosphatases in the development of human cancer have only emerged in the last decade. In this review, we discuss the data obtained from studies examining the biological and pathological roles of a serine/threonine protein phosphatase, PP5, which suggest that PP5 is a potentially important regulator of both hormone- and stress-induced signaling networks that enable a cell to respond appropriately to genomic stress.
Cancer Metastasis Rev 2008 Jun
PMID:The role of serine/threonine protein phosphatase type 5 (PP5) in the regulation of stress-induced signaling networks and cancer. 1825 12

Protein tyrosine phosphatase, PTPL1, (also known as PTPN13, FAP-1, PTP-BAS, PTP1E) is a non-receptor type PTP and, at 270 kDa, is the largest phosphatase within this group. In addition to the well-conserved PTP domain, PTPL1 contains at least 7 putative macromolecular interaction domains. This structural complexity indicates that PTPL1 may modulate diverse cellular functions, perhaps exerting both positive and negative effects. In accordance with this idea, while certain studies suggest that PTPL1 can act as a tumor-promoting gene other experimental studies have suggested that PTPL1 may function as a tumor suppressor. The role of PTPL1 in the cancer cell is therefore likely to be both complex and context dependent with possible roles including the modulation of growth, stress-response, and cytoskeletal remodeling pathways. Understanding the nature of molecular complexes containing PTPL1, its interaction partners, substrates, regulation and subcellular localization are key to unraveling the complex personality of this protein phosphatase.
Cancer Metastasis Rev 2008 Jun
PMID:PTPL1: a large phosphatase with a split personality. 1826 46

The NF-AT transcription factors regulated by the phosphatase calcineurin play a role in breast cancer metastasis-promoting tumor cell invasion. Metastasis is a multistep process requiring angiogenesis and endothelial activation. NF-AT is also expressed in endothelial cells, and calcineurin-NF-AT signaling is an important downstream effector of the proangiogenic cytokine VEGF. One isoform of the endogenous calcineurin regulator, Down syndrome candidate region-1 (DSCR1.Ex4), suppresses calcineurin-NFAT signaling blocking endothelial proliferation. However, overexpression of the other DSCR1 isoform (DSCR1.Ex1) may promote angiogenesis. We report that targeted deletion of both isoforms leads to hyperactivated calcineurin and precocious endothelial apoptosis, inhibiting formation of an effective tumor vasculature and suppressing tumorigenesis. Treatment with the specific pharmacological calcineurin inhibitor cyclosporin A rescues this endothelial defect in DSCR1(-/-) mice, restoring tumor growth.
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PMID:Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth. 1845 25

Recent improvements in immunosuppressive therapies have reduced the incidence of acute rejection and increased patient survival. These agents may however contribute to higher rates of mortality due to an increased risk of cardiovascular disease or malignancy. Transplant patients are immunocompromised with a reduced ability to combat the development of malignancy. The higher risk for the activity of oncoviruses may also contribute to the higher incidence and determine specific tumor types. Some immunosuppressants seem to have direct oncogenic effects. In vitro data have demonstrated that calcineurin inhibitors (CNIs) may show direct effects on tumor growth and the development of metastases. In contrast, mTOR inhibitors have demonstrated anti-tumoral properties in vitro and perhaps potent anti-angiogenic effects thereby. Recent studies and registry analyses have confirmed that mTOR inhibitors are associated with a reduced incidence of malignancies. UNOS data demonstrated that an mTOR inhibitor, with or without a CNI, is associated with a reduced incidence of tumors compared to regimens without mTOR inhibitors. The Rapamune Maintenance Regimen study demonstrated that patients receiving sirolimus-based, CNI-free therapy after CsA withdrawal at 3 months showed a reduced incidence of malignancy at 5 years posttransplant, compared with those who continued on a regimen that included CsA. In the CONVERT study, patients converted to sirolimus revealed a significantly lower malignancy rate at 24 months (3.1%) compared with those who continued CNI-based therapy (9.8%, P < .001). The elimination of CNIs and the introduction of sirolimus may, therefore, have a role to reduce the risk of cancer among posttransplant patients.
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PMID:Minimizing the risk of posttransplant malignancy. 1910 Sep 6

Metastasis suppressors and other regulators of cell motility play an important role in tumor invasion and metastases. We previously identified that activation of the G protein coupled receptor 54 (GPR54) by the metastasis suppressor metastin inhibits cell migration in association with overexpression of Regulator of calcineurin 1 (RCAN1), an endogenous regulator of calcineurin. Calcineurin inhibitors also blocked cell migration in vitro and RCAN1 protein levels were reduced in nodal metastases in thyroid cancer. The purpose of the current study was to determine directly if RCAN1 functions as a motility suppressor in vitro. Several cancer cell lines derived from different cancer types with different motility rates were evaluated for RCAN1 expression levels. Using these systems we determined that reduction of endogenous RCAN1 using siRNA resulted in an increase in cancer cell motility while expression of exogenous RCAN1 reduced cell motility. In one cell line with a high migratory rate, the stability of exogenously expressed RCAN1 protein was reduced and was rescued by treatment with a proteasome inhibitor. Finally, overexpression of RCAN1 was associated with an increase in cell adhesion to collagen IV and reduced calcineurin activity. In summary, we have demonstrated that the expression of exogenous RCAN1 reduces migration and alters adhesion; and that the loss of endogenous RCAN1 leads to an increase in migration in the examined cancer cell lines. These results are consistent with a regulatory role for RCAN1 in cancer cell motility in vitro.
Clin Exp Metastasis 2009
PMID:Regulator of calcineurin 1 modulates cancer cell migration in vitro. 1930 9


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