Cain, A Novel Physiologic Protein Inhibitor of Calcineurin

Lai, Michael M.; Burnett, Patrick; Wolosker, Herman; Blackshaw, Seth; Snyder, Solomon H.

doi:10.1074/jbc.273.29.18325

Cited by 214 publications

(173 citation statements)

References 52 publications

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“…CAIN (also known as Cabdin) acts as a physiological non-competitive inhibitor of calcineurin and both proteins are components of the endocytotic machinery [50]. Overexpression of CAIN in HEK293 cells blocked endocytosis [51]. Thus decreased levels of CAIN could also favour endocytosis in insulin-producing cells.…”

Section: Discussionmentioning

confidence: 99%

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

et al. 2004

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Aims/hypothesis. Cytokines are important humoral mediators of beta cell destruction in autoimmune diabetes. The aim of this study was to identify novel cytokine-induced genes in insulin-producing RINm5F cells, which may contribute to beta cell death or survival. Methods. A global gene expression profile in cytokine-exposed insulin-producing RINm5F cells was achieved by automated restriction fragment differential display PCR. The expression of selected candidate genes was confirmed by real-time RT-PCR analysis. Results. Exposure of RINm5F cells to IL-1β or to a cytokine mixture (IL-1β, TNF-α, IFN-γ) for 6 h resulted in the differential expression of a functional gene cluster. Apart from the well-known up-regulation of the cytokine-responsive genes iNOS, NF-κB, MnSOD and Hsp70, several genes that belong to the functional cluster of the endocytotic pathway were identified. These endocytotic genes comprised: clathrin, megalin, synaptotagmin and calcineurin, which were up-regulated by IL-1β or the cytokine mixture.In contrast, the expression of the calcineurin inhibitor CAIN and of the GDP/GTP exchange protein Rab3 was down-regulated by cytokines. Other up-regulated cytokine-responsive genes were: agrin, murine adherent macrophage protein mRNA (MAMA) and transport-associated protein (TAP1/MTP), whereas the plasma membrane calcium ATPase (PMCA) 2 and PMCA 3 genes were down-regulated by cytokines. Conclusions/interpretation. Our results indicate that genes of the endocytotic pathway are regulated by pro-inflammatory cytokines. This might affect the density of cytokine receptors at the beta cell surface and concomitantly the sensitivity of the cells to cytokine toxicity. A better understanding of the functional cross-talk between endocytotic and cytokine signalling pathways could further the development of novel strategies to protect pancreatic beta cells against toxic effects of pro-inflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

et al. 2004

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“…Alternatively, it is possible that CnABP is a substrate for calcineurin with its own NFAT-independent cellular activity, as is the case for the K + channel TRESK (54). In this respect, it is remarkable that the best-conserved domain of CnABP contains a perfect PxIxIT consensus sequence (where x represents any amino acid), which is a calcineurin docking site found in NFATs and other calcineurin substrates (54,55), as well as in calcineurin inhibitor proteins such as Cain/Cabin1 and A238L (56)(57)(58). This sequence was shown to be sufficient for binding to calcineurin (59).…”

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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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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“…It has been reported that in response to PKC activation Cabin 1 becomes hyperphosphorylated exhibiting a higher affinity for calcineurin, and the binding of Cabin 1 to the enzyme inhibits its activity (7,9). To investigate the possible role of Cabin 1 in this signalling pathway, Cabin 1 was immunoprecipitated with a polyclonal antibody.…”

Section: Cabin 1 As a Signal Transducer Between Pkc And Calcineurinmentioning

confidence: 99%

“…Cabin 1 is hypophosphorylated in non-activated T cells, and in response to protein kinase C (PKC) activation, it becomes hyperphosphorylated exhibiting a higher affinity for calcineurin. It has been reported that the interaction between Cabin 1 and calcineurin requires both calcium signalling and activation of PKC (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

The role of protein kinase C isoenzymes in the regulation of calcineurin activity in human peripheral blood mononuclear cells

et al. 2007

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Abstract. It is known that PMA (phorbol-12-myristate-13-acetate) can activate the classical and novel protein kinase C isoenzymes (cPKC α, ß, γ and nPKC δ, ε, η, θ), while the calcium ion can induce only the activity of cPKC. Calcineurin binding protein (Cabin 1) belongs to the group of endogenous inhibitors of calcineurin. Cabin 1 becomes hyperphosphorylated in response to PKC activation and may play a negative role in calcineurin signalling. It was observed that both PMA treatment and the increase in intracellular Ca 2+ contributed to the reduction of calcineurin activity in human peripheral blood mononuclear cells without modulating the mRNA and the protein levels of calcineurin. PMA and Caionophore (A23187), the activating agents of PKC, applied alone or in combination, significantly increased the phosphorylation state of Cabin 1 as revealed by immunoprecipitation of Cabin 1 detecting its phospho-Ser content by specific antibodies. GF109203X, an inhibitor of the classic and the novel protein kinase C isoenzymes, and Gö6976, the selective inhibitor of the classical cPKC isoenzymes were able to abolish the effect of PMA or/and Ca-ionophore on the calcineurin activity with concomitant reversal of the hyperphosphorylation of Cabin 1. The calcineurin/Cabin 1 system was not influenced by Rottlerin, an inhibitor of PKC δ isoenzyme either in the absence or in the presence of Caionophore and PMA. We presented evidence for the prominent role of cPKC α, ß, γ isoenzymes in the inhibition of calcineurin as induced by PMA and Ca-ionophore. We demonstrated also that hyperphosphorylation of Cabin 1 by PMA/Ca 2+ -activated cPKC isoenzymes resulted in a simultaneous inhibition of calcineurin in peripheral blood mononuclear cells. These results suggest a negative regulatory role for Cabin 1 in calcineurin signalling and provide a possible mechanism of feedback inhibition through cross-talk between PKC and calcineurin.

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Cain, A Novel Physiologic Protein Inhibitor of Calcineurin

Cited by 214 publications

References 52 publications

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

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

The role of protein kinase C isoenzymes in the regulation of calcineurin activity in human peripheral blood mononuclear cells

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