An Emerging Role for Ca2+/Calcineurin/NFAT Signaling in Cancerogenesis

Buchholz, Malte; Ellenrieder, Volker

doi:10.4161/cc.6.1.3650

Cited by 59 publications

(59 citation statements)

References 45 publications

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“…**, P < 0.01; ***, P < 0.001. migration and proliferation. At the molecular level, we identified CnABP as an inhibitor of calcineurin Aβ, the catalytic subunit of a phosphatase known to act as an intermediate of calcium signaling involved in proliferation and migration (41)(42)(43)(44)(45). Together, these results suggest a role for CnABP in the oncogenic program leading to WTs.…”

Section: Knockdown Of Cnabp In Achn Cells Bymentioning

confidence: 57%

“…We showed that CnABP interacts with calcineurin Aβ and interferes with its phosphatase activity as well as with its downstream NFAT-dependent nuclear response. At the cellular level, calcineurin-NFAT signaling has been associated with different outcomes such as increased proliferation and migration (42,44,45). This pathway was shown to play an important role CnABP expression strongly inhibits ionomycin-induced NFATc3 nuclear translocation.…”

Section: Regulation Of Calcineurin Signaling By Cnabpmentioning

confidence: 99%

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Calcineurin A–Binding Protein, a Novel Modulator of the Calcineurin-Nuclear Factor of Activated T-Cell Signaling Pathway, Is Overexpressed in Wilms' Tumors and Promotes Cell Migration

Nguyen

Béland²,

Gaitan³

et al. 2009

Molecular Cancer Research

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Current therapeutic strategies against Wilms' tumor (WT) reach 80% to 85% success rate. In spite of this, a remaining 15% to 20% of tumors relapse and are associated with increased metastasis and poor prognosis. To identify new regulators of WT progression, we screened for developmental target genes of Pax2, a key regulator of kidney development and a WT signature gene. We show that one of these target genes, calcineurin A-binding protein (CnABP), is coexpressed with Pax2 during kidney development and is overexpressed in >70% of WT samples analyzed. The CnABP gene encodes a novel protein product conserved in higher vertebrates. We show that CnABP promotes cell proliferation and migration in cell culture experiments. Biochemical analyses additionally identified an interaction between CnABP and calcineurin Aβ, the catalytic subunit of the calcium-responsive serine/ threonine phosphatase calcineurin. We show that this interaction leads to the inhibition of calcineurin phosphatase activity and prevents nuclear factor of activated T-cell (NFAT) nuclear translocation. Inhibition of NFAT nuclear localization results in decreased NFAT transcriptional response. Together, these data identify a new modulator of calcineurin signaling up-regulated in WTs. (Mol Cancer Res 2009;7(6):821-31)

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Section: Knockdown Of Cnabp In Achn Cells Bymentioning

confidence: 57%

Section: Regulation Of Calcineurin Signaling By Cnabpmentioning

confidence: 99%

Calcineurin A–Binding Protein, a Novel Modulator of the Calcineurin-Nuclear Factor of Activated T-Cell Signaling Pathway, Is Overexpressed in Wilms' Tumors and Promotes Cell Migration

Nguyen

Béland²,

Gaitan³

et al. 2009

Molecular Cancer Research

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“…Mice expressing an NFAT allele with increased affinity for calcineurin exhibit developmental abnormalities (8). Alterations in calcineurin activity have been linked to multiple human diseases including cardiac hypertrophy (9,10), cancer (11,12), and neurodegeneration (13). Inhibition of calcineurin phosphatase activity underlies the therapeutic action of the immunosuppressants tacrolimus and cyclosporine A, which have been extensively administered to patients to prevent organ transplant rejection (14).…”

Section: Camentioning

confidence: 99%

Regulatory Subunit Myristoylation Antagonizes Calcineurin Phosphatase Activation in Yeast

Connolly

Kingsbury

2012

Journal of Biological Chemistry

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“…The calcineurin pathway is so important for T cell proliferation that FK506 and cyclosporin are widely used as immunosuppressants (31,32). In addition to immune cells, members of the NFAT family are also expressed in a wide range of other cell types where they are implicated in cell cycle progression, cell development and differentiation, angiogenesis, and tumorigenesis (33,34). The NFAT family comprises four members, among which NFATc1 plays a key role in cell growth as shown by the phenotype of the NFATc1 KO mice, which exhibits serious B and T lymphocyte, cardiomyocyte, and osteoblast deficit (35).…”

mentioning

confidence: 99%

“…The NFAT family comprises four members, among which NFATc1 plays a key role in cell growth as shown by the phenotype of the NFATc1 KO mice, which exhibits serious B and T lymphocyte, cardiomyocyte, and osteoblast deficit (35). Moreover, NFATc1 is activated in pancreatic cancer overexpressing the c-myc oncogene (34) and is implicated in resistance to apoptosis (36) and in tumor invasiveness (37).…”

mentioning

confidence: 99%

Expression of the P2X7 Receptor Increases the Ca2+ Content of the Endoplasmic Reticulum, Activates NFATc1, and Protects from Apoptosis

Adinolfi¹,

Callegari²,

Cirillo

et al. 2009

Journal of Biological Chemistry

109

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The P2X 7 receptor is known for the cytotoxic activity because of its ability to cause opening of non-selective pores in the plasma membrane and activate apoptotic caspases. A key factor of P2X 7 -dependent cytotoxicity is the massive intracellular Ca 2؉ increase triggered by its activation. Here we show that P2X 7 transfection increased the ability of the endoplasmic reticulum to accumulate, store, and release Ca 2؉ . This caused a larger agonist-stimulated increase in cytosol and mitochondrial Ca 2؉ in P2X 7 transfectants than in mock transfected cells. P2X 7 transfectants survived and even proliferated in serum-free conditions and were resistant to apoptosis triggered by ceramide, staurosporin, or intracellular Zn 2؉ chelation. Finally, the nuclear factor of activated T cells complex 1 (NFATc1) was strongly activated in the P2X 7 transfectants. These observations support our previous finding that the P2X 7 receptor under tonic conditions of stimulation, i.e. those observed in response to basal ATP release, has an anti-apoptotic or even growth promoting rather than cytotoxic activity.Cell responses to extracellular ATP are mediated by P2 receptors: ionotropic P2X and metabotropic P2Y (1). The P2X 7 receptor (P2X 7 R) 4 subtype stands out in the P2X subfamily for its ability to trigger a host of physiologic or pathologic responses: plasma membrane blebbing (2, 3), rapid release of interleukin-1␤ via microvesicle shedding (2, 4), cell fusion (5), lymphoid cell proliferation (6), cell death (7,8), and bone formation/ resorption (9). This receptor is characterized by low affinity for ATP and by two states of permeability (10, 11). At high micromolar ATP concentrations, P2X 7 behaves as a cation-selective channel, whereas a prolonged exposure to nearly millimolar concentrations triggers the transition to a nonselective pore that admits hydrophilic solutes of molecular mass up to 900 Da (12-14). A common feature of both conductance states is a strong elevation of free cytoplasmic calcium levels ([Ca 2ϩ ] i ), a response critical for the biological role of this receptor.Recent evidence from our group shows that basal levels of ATP, naturally present in the extracellular milieu, cause a tonic activation of the P2X 7 R, which in turn triggers [Ca 2ϩ ] i increase and Ca 2ϩ entry into the mitochondria. The increased intramitochondrial Ca 2ϩ concentration ([Ca 2ϩ ] mt ) then enhances mitochondrial potential, increases ATP synthesis, and promotes survival and proliferation in the absence of serum (15). Increased mitochondrial potential and ability to grow under serum-free conditions are hallmark of tumor transformation (16). Furthermore, overexpression of the P2X 7 R is associated with several cancers or growth disturbances such as chronic lymphocytic leukemia (17), prostate (18)

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An Emerging Role for Ca2+/Calcineurin/NFAT Signaling in Cancerogenesis

Cited by 59 publications

References 45 publications

Calcineurin A–Binding Protein, a Novel Modulator of the Calcineurin-Nuclear Factor of Activated T-Cell Signaling Pathway, Is Overexpressed in Wilms' Tumors and Promotes Cell Migration

Calcineurin A–Binding Protein, a Novel Modulator of the Calcineurin-Nuclear Factor of Activated T-Cell Signaling Pathway, Is Overexpressed in Wilms' Tumors and Promotes Cell Migration

Regulatory Subunit Myristoylation Antagonizes Calcineurin Phosphatase Activation in Yeast

Expression of the P2X7 Receptor Increases the Ca2+ Content of the Endoplasmic Reticulum, Activates NFATc1, and Protects from Apoptosis

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