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)

Increasing phosphorylation reactions by protein kinase A (PKA) or reducing dephosphorylation reactions of protein phosphatase-2A (PP-2A) increases the invasiveness of Lewis lung carcinoma (LLC) cells, as measured by their capacity to traverse extracellular matrix (ECM)-coated filters. Metastatic LLC-LN7 variants have reduced PP-2A activity when compared to nonmetastatic LLC-C8 variants. Immunoblotting showed that this reduced level of PP-2A activity was not due to reduced levels of the PP-2A catalytic (C) subunit. The cellular PP-2A activity could be stimulated by addition of C2-ceramide to LLC-LN7 lysates, or by incubating cells with either C2-ceramide or with a noncalcemic analog of vitamin D3, which has previously been shown to stimulate the release of ceramide. These treatments to elevate PP-2A activity in metastatic LLC-LN7 cells resulted in a decline in their capacity to invade through select (ECM) components, particularly through vitronectin and laminin. Underscoring the importance of PP-2A in limiting the invasiveness of tumor cells was the demonstration that LLC-LN7 cell transfectants overexpressing the PP-2A C alpha subunit were less invasive through ECM components than the wild-type cells. Invasion by these cells was further reduced by additionally increasing PP-2A activity by incubation with C2-ceramide or the vitamin D3 analog. These results suggest a role of a vitamin D3/ceramide/PP-2A pathway in limiting the invasiveness of tumor cells through select ECM components.
Invasion Metastasis 1996
PMID:Vitamin D3 and ceramide reduce the invasion of tumor cells through extracellular matrix components by elevating protein phosphatase-2A. 937 Dec 27

Metastatic Lewis lung carcinoma (LLC-LN7) variants have previously been shown to have reduced levels of protein phosphatase-2A (PP-2A) activity as compared to the nonmetastatic LLC-C8 cells. The present study showed that inhibition of PP-2A in the nonmetastatic LLC-C8 cells caused a rapid change from a spread to a rounded morphology and increased their in vitro invasiveness through laminin. In contrast, the metastatic LLC-LN7 cells were rounded and invasive, which was not affected by inhibition of PP-2A. To determine whether these differences could be attributed to alterations in PP-2A association with the cytoskeleton, the extent of PP-2A colocalization with microtubules was tested. Immunostaining for tubulin showed prominent filamentous fibers in nonmetastatic LLC-C8 cells and small foci of PP-2A immunostaining along these microtubules. In contrast, the tubulin staining was diffuse throughout the metastatic LLC-LN7 cells and there was little evidence of association with PP-2A. Western blot analyses showed that this reduced level of PP-2A association with microtubules in metastatic LLC-LN7 cells was not due to differences in levels of the PP-2A subunits. Instead, it may be due to the reduced association of the subunits into the heterotrimeric form of the PP-2A holoenzyme. These studies show the importance of PP-2A in maintaining a spread morphology and in restricting invasiveness, and a loss of this regulatory control in metastatic cells. This loss of PP-2A regulatory control in metastatic cells may be due to a reduction in the trimeric form of the PP-2A holoenzyme.
Invasion Metastasis 1997
PMID:Protein phosphatase-2A associates with the cytoskeleton to maintain cell spreading and reduced motility of nonmetastatic Lewis lung carcinoma cells: the loss of this regulatory control in metastatic cells. 977 92

Cancers, such as human head and neck squamous cell carcinomas (HNSCC), have been shown to stimulate angiogenesis by their production of endothelial cell proliferative and motility-stimulatory factors. The present studies to elucidate the intracellular mechanisms that contribute to the motility response of endothelial cells to HNSCC-derived factors showed a decline in the organization of actin filaments and microtubules. This HNSCC-induced decline in cytoskeletal organization coincided with the downregulation of endothelial cell protein phosphatase-1 and 2A (PP-1/2A) activities, and could be mimicked by directly inhibiting these enzyme activities with okadaic acid. These results show that the increased motility of endothelial cells in response to HNSCC-derived angiogenic factors involves downregulation of PP-1/2A activities and, consequently, a decline in cytoskeletal organization.
Invasion Metastasis 1997
PMID:Endothelial cell response to human head and neck squamous cell carcinomas involves downregulation of protein phosphatases-1/2A, cytoskeletal depolymerization and increased motility. 977 93

The PTEN tumor suppressor gene encodes a dual-specificity protein phosphatase that may play a key role in modulating integrin-mediated signals. Inactivation of the PTEN gene has been detected in a small percentage of clinically localized prostate cancers but is common in metastatic disease. It has been shown in glioblastoma cell lines that loss of chromosome 10q, where the PTEN gene is located, is associated with increased angiogenic activity in the conditioned medium attributable to downregulation of thrombospondin-1, a negative regulator of angiogenesis. Therefore, we wished to determine whether inactivation of PTEN might be associated with increased angiogenesis in prostate cancers, because increased angiogenesis in localized cancers is associated with development of metastatic disease. Angiogenesis was assessed by counting microvessels in areas of maximal neovascularization after immunostaining with anti-factor VIII-related antigen antibodies in eight cases with proven homozygous deletion of the PTEN gene and 24 control cases. There was a statistically significant correlation between PTEN inactivation and increased microvessel counts. The microvessel density was higher at all Gleason scores in the cases with PTEN inactivation compared with control cases with the same score. To determine whether the increased angiogenesis in cases with PTEN inactivation was caused by downregulation of expression of the angiogenesis inhibitor thrombospondin-1, we analyzed a subset of the cases by immunostaining with anti-thrombospondin-1 antibody. Approximately 25% of cases showed decreased staining of prostate cancer cells, but there was no correlation with PTEN inactivation. Thus, PTEN inactivation is associated with increased angiogenesis, but the increased angiogenesis is not attributable to downregulation of thrombospondin-1 expression.
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PMID:Inactivation of the PTEN tumor suppressor gene is associated with increased angiogenesis in clinically localized prostate carcinoma. 1020 63

A tumor suppressor gene at 10q 23.3, designated PTEN, encoding a dual specificity phosphatase with lipid and protein phosphatase activity, has been shown to play an important role in the pathogenesis of a variety of human cancers. Germline mutations in PTEN cause Cowden syndrome (CS), which is characterized by multiple hamartomas and a high risk of breast and thyroid cancers. Frequent loss of heterozygosity at 10q is found in both early and advanced-stage sporadic melanomas; however, mutations or deletions in PTEN are detected mainly in melanoma cell lines. In this study, we examined PTEN expression in 34 unselected sporadic melanomas (4 primary melanomas, 30 metastases) using immunohistochemistry and correlated this with the results of structural studies of this gene. Immunostaining of 34 melanoma samples revealed no PTEN expression in 5 (15%) and low PTEN expression in 17 (50%), whereas the rest of the tumors (35%) had high levels of expression. Hemizygous deletion was found in 32% of the tumors but neither intragenic PTEN mutation nor biallelic deletion was found in any of the samples. Of the 5 melanomas showing no PTEN expression, 4 had no mutation or deletion of PTEN. Of the 13 tumors having weak PTEN immunoreactivity and informative loss of heterozygosity results, 6 had evidence of hemizygous allelic loss of PTEN while the remaining 7 had intact PTEN. These results strongly support PTEN as a major tumor suppressor on 10q involved in melanoma tumorigenesis and suggest an epigenetic mechanism of biallelic functional inactivation not previously observed in other cancers where PTEN might be involved.
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PMID:Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. 1102 16

Motility and adhesiveness are regulated by a multitude of factors, including cytoskeletal polymerization and phosphorylation of cytoskeletal and associated proteins. The metastatic Lewis lung carcinoma variant, LLC-LN7, was highly motile in vitro and had lower levels of the serine/threonine protein phosphatase PP-2A than did the nonmetastatic variant, LLC-C8. Reducing PP-2A activity of the nonmetastatic cells pharmacologically or with catalytic (Calpha) subunit antisense increased their in vitro motility. Nonmetastatic LLC-C8 cells had a greater proportion of polymerized tubulin which co-purified with PP-2A as compared to the metastatic LLC-LN7 cells. The PP-2A that was associated with the microtubules of these cells showed similar ratios of the Aalpha structural subunit to the Calpha/beta catalytic subunits. In contrast, the proportion of the regulatory subunit B56alpha was lower in the nonmetastatic LLC-C8 cells as compared to the metastatic LLC-LN7 cells. These studies show the role of PP-2A in restricting the motility of nonmetastatic tumor cells and suggest that the loss of this regulatory control in metastatic LLC-LN7 cells may be due to both a reduction in microtubule-associated PP-2A and a difference in the composition of the subunits of PP-2A that is associated with the microtubules.
Clin Exp Metastasis 2000
PMID:Differences in association of the serine/threonine protein phosphatase PP-2A with microtubules of metastatic and nonmetastatic tumor cells. 1146 73

Cellular adhesion and motility, processes regulated by focal adhesion assembly and disassembly, can influence a tumor cell's ability to metastasize. Focal adhesion dynamics are, in turn, influenced by the serine and tyrosine phosphorylation state of paxillin. Using Lewis lung carcinoma (LLC) tumor variants, this study shows the importance of the serine/threonine protein phosphatase-2A (PP-2A) in maintaining adherence and restricting tumor cell motility, and modulating the serine and tyrosine phosphorylation of paxillin. Treating non-metastatic LLC-C8 tumor variants with okadaic acid to inhibit PP-2A activity resulted in cell rounding and increased motility. These effects on motility and adherence were accompanied by increased serine and decreased tyrosine phosphorylation of paxillin. These results suggest PP-2A regulation of paxillin phosphorylation may have a role in controlling tumor cell adherence and motility.
Clin Exp Metastasis 2002
PMID:Protein phosphatase-2A modulates the serine and tyrosine phosphorylation of paxillin in Lewis lung carcinoma tumor variants. 1219 69

Cellular adherence and motility are processes that are controlled by focal adhesion assembly and disassembly. Consequently, the dynamics of focal adhesions regulate tumor cell metastasis and are influenced by the tyrosine phosphorylation state of paxillin. Metastatic LLC cells are more migratory and have reduced paxillin tyrosine phosphorylation as compared to nonmetastatic LLC cells. In nonmetastatic Lewis lung carcinoma (LLC) tumor cells, inhibition of the serine/threonine protein phosphatase-2A (PP-2A) activity results in increased motility that is associated with a reduction in the phosphotyrosine content of paxillin. Studies to determine if PP-2A can regulate protein tyrosine phosphatase activity showed that blocking PP-2A activity of nonmetastatic LLC-C8 tumor cells with okadaic acid reduces protein tyrosine phosphatase activity. Among the tyrosine phosphatases whose activity was inhibited upon PP-2A inhibition is Shp-2. In contrast, protein levels of Shp-2 are unaffected by PP-2A inhibition. While these results do not fully identify how inhibition of PP-2A results in tyrosine dephosphorylation of paxillin, they do demonstrate that PP-2A can link serine/threonine and tyrosine signaling pathways by regulating protein tyrosine phosphatases.
Clin Exp Metastasis 2003
PMID:Protein phosphatase-2A regulates protein tyrosine phosphatase activity in Lewis lung carcinoma tumor variants. 1285 23

Epidemiology is a very reliable science for the identification of carcinogens. Epidemiological studies require that the effect, cancer in this case, has already occurred, when of course it would be more desirable to identify potential carcinogenic substances at an earlier stage before they have caused a large number of malignancies and thus become identifiable by epidemiological studies. In the past 30 years, molecular pathology (which includes chemistry, biochemistry, molecular biology, molecular virology, molecular genetics, epigenetics, genomics, proteomics, and other molecular-based approaches) has identified some key alterations that are required for cellular transformation and malignancy. Agents that specifically interfere with some of these mechanisms are suspected human carcinogens. It can be stated that tumor formation requires the following steps: (1) inactivation of Rb and p53 cellular pathways; (2) activation of Ras and/or other growth promoting pathways; (3) inactivation of phosphatase 2A that causes changes in the phosphorylation and activity of several cellular proteins; (4) evasion of apoptosis; (5) telomerase activation or alternative mechanisms of cellular immortalization; (6) angiogenic activity; and (7) the ability to invade surrounding tissues and to metastasize. Here, we review the molecular mechanisms of cellular transformation. The integration of this knowledge with classical epidemiology and animal studies should permit a more rapid and accurate identification of human carcinogens.
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PMID:Epidemiology and molecular pathology at crossroads to establish causation: molecular mechanisms of malignant transformation. 1532 19

PTEN is a dual-specificity phosphatase with both protein phosphatase and lipid phosphatase activity. PTEN is the first phosphatase identified as a tumor suppressor. Not since the discovery of p53 has a tumor suppressor generated such interest. Initial studies performed on cancer cell lines suggested that PTEN may be responsible for almost all types of cancer, both solid tumors and hematological malignancies. Biallelic deletion of PTEN has been associated with advanced stage tumors or metastatic disease. PTEN has been shown to play a pivotal role in apoptosis, cell cycle arrest, and possibly cell migration. Emerging data suggest that this may be an oversimplification of PTEN's role, and that PTEN may be haploinsufficient for tumor progression and may play important roles in other cellular functions such as angiogenesis and MAP kinase signaling.
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PMID:PTEN regulatory functions in tumor suppression and cell biology. 1544 14


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