Cyclosporin A Inhibits Calcineurin/Nuclear Factor of Activated T-Cells Signaling and Induces Apoptosis in Retinoblastoma Cells

Eckstein, L.; Quill, K.R. Van; Bui, Steven; Uusitalo, Marita; O’Brien, Joan M.

doi:10.1167/iovs.04-1022

Cited by 47 publications

(28 citation statements)

References 63 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: 78%

“…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: 78%

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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“…16 In T cells, NFATc1 upregulation attenuates CsA-in- duced apoptosis in several cell types 11,17,18 ; therefore, we hypothesized that NFATc1 protected PTCs from apoptosis associated with AKI. We quantified terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling (TUNEL)-positive PTCs and showed a significant increase in apoptotic PTC in Nfatc1 ϩ/Ϫ mice compared with WT mice (P ϭ 0.0431, two-way ANOVA).…”

Section: Nfatc1 Attenuation Results In Increased Ptc Apoptosismentioning

confidence: 99%

“…Previously, administration of higher dosages (100 mg/kg CsA) did not induce functional or structural abnormalities 20 ; however, CsA-treated Nfatc1 ϩ/Ϫ mice and 10-mg/kg CsA-treated WT mice caused increased PTC apoptosis, decreased proliferation, renal failure, and death after HgCl 2 -induced AKI. CsA inhibition of NFATc1 activity has been previously associated with increased apoptosis and reduced cell proliferation in monocytes, 17 retinoblastoma, 18 and T cells. 11 Furthermore, ectopic expression of a constitutively active isoform of NFATc1 protected cells from apoptosis and promoted proliferation, 21 and expression of the autoregulated NFATc1/A isoform attenuated induced cell death in T cells.…”

Section: Discussionmentioning

confidence: 96%

NFATc1 Identifies a Population of Proximal Tubule Cell Progenitors

Langworthy

Zhou

Caestecker

et al. 2009

Journal of the American Society of Nephrology

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Recovery from acute kidney injury requires regeneration of tubule cells. Because calcineurin induces nuclear transport of NFATc proteins, whose expression pattern correlates with the nephron segments injured by calcineurin inhibitors, we hypothesized that NFATc1 plays a role in modifying epithelial regeneration after injury. To test this, we induced proximal tubular cell (PTC) injury in Balb/c mice and Nfatc1 ϩ/Ϫ mice with mercuric chloride; the PTCs of Nfatc1 ϩ/Ϫ mice demonstrated increased apoptosis, sustained injury, and delayed regeneration. To attenuate NFATc1 activity further, we injected cyclosporin A daily. Cyclosporin A-treated Nfatc1 ϩ/Ϫ mice demonstrated rapid and severe injury after administration of mercuric chloride, with increased serum creatinine, increased apoptosis, decreased PTC proliferation, and increased mortality compared with similarly treated wild-type mice. Using a novel NFATc1 transgenic line that reports activation of an NFATc1 enhancer domain critical for NFATc1 autoamplification, we demonstrated accentuated NFATc1 expression in a PTC subpopulation after mercuric chloride-induced injury. In addition, NFATc1-labeled, apoptosis-resistant PTCs proliferated to repair the damaged proximal tubule segment. These data provide evidence for a resident progenitor PTC population and suggest a role for NFATc1 in the regeneration of injured proximal tubules.

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“…However, the polymorphic variants, in agreement with the microarray experiment, repressed basal NFTAT4 and cdc25a transcription, lending further support to the hypothesis that the polymorphisms might transform B-MYB in a mild dominant-negative molecule (Figure 3). NFAT4 is a transcription factor that promotes cell survival and cdc25a is a component of the cell cycle machinery often overexpressed in human cancer (Oukka et al, 1998;Eckstein et al, 2005;Boutros et al, 2006). Together, these results suggest that the polymorphisms induce a change of protein conformation that partially inactivates B-MYB function.…”

Section: Functional Characterization Of B-myb Polymorphismsmentioning

confidence: 86%

Isolation and functional assessment of common, polymorphic variants of the B-MYB proto-oncogene associated with a reduced cancer risk

Schwab¹,

Bussolari

Corvetta

et al. 2007

Oncogene

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The B-MYB proto-oncogene is a transcription factor belonging to the MYB family that is frequently overexpressed or amplified in different types of human malignancies. While it is suspected that B-MYB plays a role in human cancer, there is still no direct evidence of its causative role. Looking for mutations of the B-MYB gene in human cell lines and primary cancer samples, we frequently isolated two nonsynonymous B-MYB polymorphic variants (rs2070235 and rs11556379). Compared to the wild-type protein, the B-MYB isoforms display altered conformation, impaired regulation of target genes and decreased antiapoptotic activity, suggesting that they are hypomorphic variants of the major allele. Importantly, the B-MYB polymorphisms are common; rs2070235 and rs11556379 are found, depending on the ethnic background, in 10-50% of human subjects. We postulated that, if B-MYB activity is important for transformation, the presence of common, hypomorphic variants might modify cancer risk. Indeed, the B-MYB polymorphisms are underrepresented in 419 cancer patients compared to 230 controls (odds ratio 0.53; (95%) confidence interval 0.385-0.755; P ¼ 0.001). This data imply that a large fraction of the human population is carrier of B-MYB alleles that might be associated with a reduced risk of developing neoplastic disease.

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Cyclosporin A Inhibits Calcineurin/Nuclear Factor of Activated T-Cells Signaling and Induces Apoptosis in Retinoblastoma Cells

Abstract: These results demonstrate functional integrity of the CN/NFAT signaling cascade in RB cells and suggest that CSA is cytotoxic to RB cells through inhibition of this pathway and consequent apoptosis induction.

Cited by 47 publications

References 63 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

NFATc1 Identifies a Population of Proximal Tubule Cell Progenitors

Isolation and functional assessment of common, polymorphic variants of the B-MYB proto-oncogene associated with a reduced cancer risk

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