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Jeffery D. Molkentin - One of the best experts on this subject based on the ideXlab platform.
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Calcineurin and NFAT4 Induce Chondrogenesis
Journal of Biological Chemistry, 2002Co-Authors: Masuhiro Tomita, Jeffery D. Molkentin, Martina I. Reinhold, Michael C. NaskiAbstract:Abstract Nuclear factor of activated T-cells (NFAT) and Calcineurin are essential regulators of immune cell and mesenchymal cell differentiation. Here we show that elevated intracellular calcium induces chondrogenesis through a Calcineurin/NFAT signaling axis that activates bone morphogenetic protein (BMP) expression. The calcium ionophore, ionomycin, induced chondrogenesis through activation of Calcineurin. The Calcineurin substrate, NFAT4, also induced chondrogenesis and chondrocyte gene expression. Significantly, the BMP antagonist, noggin, or dominant negative BMP receptors blocked the effects of elevated intracellular calcium on chondrogenesis. This suggested that Calcineurin/NFAT4 activates BMP expression. Consistent with this, BMP2 gene expression was increased by ionomycin and suppressed by the Calcineurin inhibitor, cyclosporine A. Furthermore, activated NFAT4 induced BMP2 gene expression. These results have important implications for the effects of NFATs during development and adaptive responses.
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Calcineurin enhances mapk phosphatase 1 expression and p38 mapk inactivation in cardiac myocytes
Journal of Biological Chemistry, 2001Co-Authors: Jeffery D. MolkentinAbstract:Abstract Multiple intracellular signaling pathways have been shown to regulate the hypertrophic growth of cardiac myocytes including mitogen-activated protein kinase (MAPK) and Calcineurin-nuclear factor of activated T-cells. However, it is uncertain if individual regulatory pathways operate in isolation or if interconnectivity between unrelated pathways is required for the orchestration of the entire hypertrophic response. To this end, we investigated the interconnectivity between Calcineurin-mediated cardiac myocyte hypertrophy and p38 MAPK signaling in vitro andin vivo. We show that Calcineurin promotes down-regulation of p38 MAPK activity and enhances expression of the dual specificity phosphatase MAPK phosphatase-1 (MKP-1). Transgenic mice expressing activated Calcineurin in the heart were characterized by inactivation of p38 and increased MKP-1 expression during early postnatal development, before the onset of cardiac hypertrophy. In vitro, cultured neonatal cardiomyocytes infected with a Calcineurin-expressing adenovirus and stimulated with phenylephrine demonstrated reduced p38 phosphorylation and increased MKP-1 protein levels. Activation of endogenous Calcineurin with the calcium ionophoreA23187 decreased p38 phosphorylation and increased MKP-1 protein levels. Inhibition of endogenous Calcineurin with cyclosporin A decreased MKP-1 protein levels and increased p38 activation in response to agonist stimulation. To further investigate potential cross-talk between Calcineurin and p38 through alteration in MKP-1 expression, the MKP-1 promoter was characterized and determined to be Calcineurin-responsive. These data suggest that Calcineurin enhances MKP-1 expression in cardiac myocytes, which is associated with p38 inactivation.
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Calcineurin promotes protein kinase c and c jun nh2 terminal kinase activation in the heart cross talk between cardiac hypertrophic signaling pathways
Journal of Biological Chemistry, 2000Co-Authors: Leon J De Windt, Thomas Force, Jeffery D. MolkentinAbstract:Abstract Multiple intracellular signaling pathways have been shown to regulate the hypertrophic growth of cardiomyocytes. Both necessary and sufficient roles have been described for the mitogen activated protein kinase1 (MAPK) signaling pathway, specific protein kinase C (PKC) isoforms, and Calcineurin. Here we investigate the interdependence between Calcineurin, MAPK, and PKC isoforms in regulating cardiomyocyte hypertrophy using three separate approaches. Hearts from hypertrophic Calcineurin transgenic mice were characterized for PKC and MAPK activation. Transgenic hearts demonstrated activation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2), but not p38 MAPK factors. Calcineurin transgenic hearts demonstrated increased activation of PKCα, β1, and θ, but not of e, β2, or λ. In a second approach, cultured cardiomyocytes were infected with a Calcineurin adenovirus to induce hypertrophy and the effects of pharmacologic inhibitors or co-infection with a dominant negative adenovirus were examined. Calcineurin-mediated hypertrophy was prevented with PKC inhibitors, Ca2+chelation, and attenuated with a dominant negative SEK-1 (MKK4) adenovirus, but inhibitors of ERK or p38 activation had no effect. In a third approach, we examined the activation of MAPK factors and PKC isoforms during the progression of load-induced hypertrophy in aortic banded rats with or without cyclosporine. We determined that inhibition of Calcineurin activity with cyclosporine prevented PKCα, θ, and JNK activation, but did not affect PKCe, β, λ, ERK1/2, or p38 activation. Collectively, these data indicate that Calcineurin hypertrophic signaling is interconnected with PKCα, θ, and JNK in the heart, while PKCe, β, λ, p38, and ERK1/2 are not involved in Calcineurin-mediated hypertrophy.
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targeted inhibition of Calcineurin prevents agonist induced cardiomyocyte hypertrophy
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Tyler Taigen, Leon J De Windt, Hae W Lim, Jeffery D. MolkentinAbstract:Cardiac hypertrophy is a major predictor of future morbidity and mortality. Recent investigation has centered around identifying the molecular signaling pathways that regulate cardiac myocyte reactivity with the goal of modulating pathologic hypertrophic programs. One potential regulator of cardiomyocyte hypertrophy is the calcium-sensitive phosphatase Calcineurin. We show here that Calcineurin enzymatic activity, mRNA, and protein levels are increased in cultured neonatal rat cardiomyocytes by hypertrophic agonists such as angiotensin II, phenylephrine, and 1% fetal bovine serum. This induction of Calcineurin activity was associated with an increase in Calcineurin Aβ (CnAβ) mRNA and protein, but not in CnAα or CnAγ. Agonist-dependent increases in Calcineurin enzymatic activity were specifically inhibited with an adenovirus expressing a noncompetitive peptide inhibitor of Calcineurin known as cain [Lai, M. M., Burnett, P. E., Wolosker, H., Blackshaw, S. & Snyder, S. H. (1998) J. Biol. Chem. 273, 18325–18331]. Targeted inhibition of Calcineurin with cain or an adenovirus expressing only the Calcineurin inhibitory domain of AKAP79 attenuated cardiomyocyte hypertrophy and atrial natriuretic factor expression in response to angiotensin II, phenylephrine, and 1% fetal bovine serum. These data demonstrate that Calcineurin is an important regulator of cardiomyocyte hypertrophy in response to certain agonists and suggest that cyclosporin A and FK506 function to attenuate cardiac hypertrophy by specifically inhibiting Calcineurin.
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Reply to revisiting Calcineurin and human heart failure
Nature Medicine, 2000Co-Authors: Hae W Lim, Jeffery D. MolkentinAbstract:We previously identified a significant increase in the content of Calcineurin protein associated with calmodulin in failed human hearts, indicative of activation3. These data are consistent with a recent report in which Calcineurin protein content was found to be increased in dilated cardiomyopathy in humans5. Since that report, we have invested considerable effort in dissecting the regulation of the three Calcineurin catalytic genes in hypertrophied and failed heart. We have determined that both the CnA- and CnA- genes are expressed in the heart and that CnA-, but not CnA-, mRNA and protein are upregulated approximately 300% by hypertrophic agonist in cultured cardiomyocytes, and that enzymatic activity is increased to a similar extent6. In vivo, we have found that Calcineurin protein content and catalytic activity are significantly increased in pressure-loaded rat hearts7. We have also re-evaluated Calcineurin activation in failed human hearts using an enzymatic phosphatase assay. In eight control human left ventricular heart samples, Calcineurin enzymatic activity was 100% 7%, compared with 171% 11% in twelve failed hearts ( P=0.007). This 71% increase in Calcineurin enzymatic activity indicates that Calcineurin activation is associated with human heart failure.
Julianne T. Djordjevic - One of the best experts on this subject based on the ideXlab platform.
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the crz1 sp1 transcription factor of cryptococcus neoformans is activated by Calcineurin and regulates cell wall integrity
PLOS ONE, 2012Co-Authors: Desmarini Desmarini, Methee Chayakulkeeree, Tania C. Sorrell, Julianne T. DjordjevicAbstract:Cryptococcus neoformans survives host temperature and regulates cell wall integrity via a calcium-dependent phosphatase, Calcineurin. However, downstream effectors of C. neoformans Calcineurin are largely unknown. In S. cerevisiae and other fungal species, a Calcineurin-dependent transcription factor Crz1, translocates to nuclei upon activation and triggers expression of target genes. We now show that the C. neoformans Crz1 ortholog (Crz1/Sp1), previously identified as a protein kinase C target during starvation, is a bona fide target of Calcineurin under non-starvation conditions, during cell wall stress and growth at high temperature. Both the Calcineurin-defective mutant, Δcna1, and a CRZ1/SP1 mutant (Δcrz1) were susceptible to cell wall perturbing agents. Furthermore, expression of the chitin synthase encoding gene, CHS6, was reduced in both mutants. We tracked the subcellular localization of Crz1-GFP in WT C. neoformans and Δcna1 in response to different stimuli, in the presence and absence of the Calcineurin inhibitor, FK506. Exposure to elevated temperature (30–37°C vs 25°C) and extracellular calcium caused Calcineurin-dependent nuclear accumulation of Crz1-GFP. Unexpectedly, 1M salt and heat shock triggered Calcineurin-independent Crz1-GFP sequestration within cytosolic and nuclear puncta. To our knowledge, punctate cytosolic distribution, as opposed to nuclear targeting, is a unique feature of C. neoformans Crz1. We conclude that Crz1 is selectively activated by calcium/Calcineurin-dependent and independent signals depending on the environmental conditions.
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The Crz1/Sp1 Transcription Factor of Cryptococcus neoformans Is Activated by Calcineurin and Regulates Cell Wall Integrity
PLOS ONE, 2012Co-Authors: Desmarini Desmarini, Methee Chayakulkeeree, Tania C. Sorrell, Julianne T. DjordjevicAbstract:Cryptococcus neoformans survives host temperature and regulates cell wall integrity via a calcium-dependent phosphatase, Calcineurin. However, downstream effectors of C. neoformans Calcineurin are largely unknown. In S. cerevisiae and other fungal species, a Calcineurin-dependent transcription factor Crz1, translocates to nuclei upon activation and triggers expression of target genes. We now show that the C. neoformans Crz1 ortholog (Crz1/Sp1), previously identified as a protein kinase C target during starvation, is a bona fide target of Calcineurin under non-starvation conditions, during cell wall stress and growth at high temperature. Both the Calcineurin-defective mutant, Δcna1, and a CRZ1/SP1 mutant (Δcrz1) were susceptible to cell wall perturbing agents. Furthermore, expression of the chitin synthase encoding gene, CHS6, was reduced in both mutants. We tracked the subcellular localization of Crz1-GFP in WT C. neoformans and Δcna1 in response to different stimuli, in the presence and absence of the Calcineurin inhibitor, FK506. Exposure to elevated temperature (30–37°C vs 25°C) and extracellular calcium caused Calcineurin-dependent nuclear accumulation of Crz1-GFP. Unexpectedly, 1M salt and heat shock triggered Calcineurin-independent Crz1-GFP sequestration within cytosolic and nuclear puncta. To our knowledge, punctate cytosolic distribution, as opposed to nuclear targeting, is a unique feature of C. neoformans Crz1. We conclude that Crz1 is selectively activated by calcium/Calcineurin-dependent and independent signals depending on the environmental conditions.
Desmarini Desmarini - One of the best experts on this subject based on the ideXlab platform.
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the crz1 sp1 transcription factor of cryptococcus neoformans is activated by Calcineurin and regulates cell wall integrity
PLOS ONE, 2012Co-Authors: Desmarini Desmarini, Methee Chayakulkeeree, Tania C. Sorrell, Julianne T. DjordjevicAbstract:Cryptococcus neoformans survives host temperature and regulates cell wall integrity via a calcium-dependent phosphatase, Calcineurin. However, downstream effectors of C. neoformans Calcineurin are largely unknown. In S. cerevisiae and other fungal species, a Calcineurin-dependent transcription factor Crz1, translocates to nuclei upon activation and triggers expression of target genes. We now show that the C. neoformans Crz1 ortholog (Crz1/Sp1), previously identified as a protein kinase C target during starvation, is a bona fide target of Calcineurin under non-starvation conditions, during cell wall stress and growth at high temperature. Both the Calcineurin-defective mutant, Δcna1, and a CRZ1/SP1 mutant (Δcrz1) were susceptible to cell wall perturbing agents. Furthermore, expression of the chitin synthase encoding gene, CHS6, was reduced in both mutants. We tracked the subcellular localization of Crz1-GFP in WT C. neoformans and Δcna1 in response to different stimuli, in the presence and absence of the Calcineurin inhibitor, FK506. Exposure to elevated temperature (30–37°C vs 25°C) and extracellular calcium caused Calcineurin-dependent nuclear accumulation of Crz1-GFP. Unexpectedly, 1M salt and heat shock triggered Calcineurin-independent Crz1-GFP sequestration within cytosolic and nuclear puncta. To our knowledge, punctate cytosolic distribution, as opposed to nuclear targeting, is a unique feature of C. neoformans Crz1. We conclude that Crz1 is selectively activated by calcium/Calcineurin-dependent and independent signals depending on the environmental conditions.
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The Crz1/Sp1 Transcription Factor of Cryptococcus neoformans Is Activated by Calcineurin and Regulates Cell Wall Integrity
PLOS ONE, 2012Co-Authors: Desmarini Desmarini, Methee Chayakulkeeree, Tania C. Sorrell, Julianne T. DjordjevicAbstract:Cryptococcus neoformans survives host temperature and regulates cell wall integrity via a calcium-dependent phosphatase, Calcineurin. However, downstream effectors of C. neoformans Calcineurin are largely unknown. In S. cerevisiae and other fungal species, a Calcineurin-dependent transcription factor Crz1, translocates to nuclei upon activation and triggers expression of target genes. We now show that the C. neoformans Crz1 ortholog (Crz1/Sp1), previously identified as a protein kinase C target during starvation, is a bona fide target of Calcineurin under non-starvation conditions, during cell wall stress and growth at high temperature. Both the Calcineurin-defective mutant, Δcna1, and a CRZ1/SP1 mutant (Δcrz1) were susceptible to cell wall perturbing agents. Furthermore, expression of the chitin synthase encoding gene, CHS6, was reduced in both mutants. We tracked the subcellular localization of Crz1-GFP in WT C. neoformans and Δcna1 in response to different stimuli, in the presence and absence of the Calcineurin inhibitor, FK506. Exposure to elevated temperature (30–37°C vs 25°C) and extracellular calcium caused Calcineurin-dependent nuclear accumulation of Crz1-GFP. Unexpectedly, 1M salt and heat shock triggered Calcineurin-independent Crz1-GFP sequestration within cytosolic and nuclear puncta. To our knowledge, punctate cytosolic distribution, as opposed to nuclear targeting, is a unique feature of C. neoformans Crz1. We conclude that Crz1 is selectively activated by calcium/Calcineurin-dependent and independent signals depending on the environmental conditions.
Anjana Rao - One of the best experts on this subject based on the ideXlab platform.
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Interaction of Calcineurin with substrates and targeting proteins.
Trends in Cell Biology, 2011Co-Authors: Anjana Rao, Patrick G. HoganAbstract:Calcineurin is a calcium activated protein phosphatase with a major role in calcium signaling in diverse cells and organs and clinical importance as the target of the immunosuppressive drugs cyclosporin A and tacrolimus (FK506). Cell biology studies have focused mainly on the role of Calcineurin in transcriptional signaling. Calcium entry in response to extracellular stimuli results in Calcineurin activation, and signal transmission from the cytosol into the nucleus through dephosphorylation and nuclear translocation of the transcription factor nuclear factor of activated T cells (NFAT). This initiates a cascade of transcriptional events involved in physiological and developmental processes. Molecular analyses of the Calcineurin–NFAT interaction have been extended recently to encompass the interaction of Calcineurin with other substrates, targeting proteins and regulators of Calcineurin activity. These studies have increased our understanding of how this essential calcium activated enzyme orchestrates intracellular events in cooperation with other signaling pathways, and have suggested a link between altered Calcineurin signaling and the developmental anomalies of Down syndrome.
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Calcineurin: from structure to function.
Current Topics in Cellular Regulation, 2001Co-Authors: Jose Aramburu, Anjana Rao, Claude B KleeAbstract:Publisher Summary The use of the Calcineurin inhibitors—namely, FK506 and CsA, together with yeast genetics and the overexpression of Calcineurin by transgenic mice, has established the critical roles of Calcineurin in the regulation of many cellular processes that are induced by changes in the concentration of intracellular Ca 2+ in response to external signals. None of the physiological roles of Calcineurin is better documented than the regulation of gene expression mediated by the broadly distributed NFAT family of transcription factors in mammalian cells. Equally well documented is the role of Calcineurin in the regulation of expression of many genes that are under the control of the TCNI/CRZl transcription factor in yeast. Calcineurim was originally identified as a major calmodulin-binding protein in the brain and later shown to be the only Ca 2+ /calmodulin-regulated serine/threonine protein phosphatase. Since then, this enzyme has been shown to be expressed in every tissue and to be highly conserved phylogenetically.
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the t cell transcription factor nfatp is a substrate for Calcineurin and interacts with fos and jun
Nature, 1993Co-Authors: Jugnu Jain, Patricia G Mccafffrey, Zoe Miner, Tom K Kerppola, John N Lambert, Gregory L Verdine, Tom Curran, Anjana RaoAbstract:TRANSCRIPTION of lymphokine genes in activated T cells is inhibited by the immunosuppressive agents cyclosporin A and FK506, which act by blocking the phosphatase activity of Calcineurin1–3. NFAT, a DNA-binding protein required for interleukin-2 gene transcription, is a potential target for Calcineurin, cyclosporin A and FK5064–11. NFAT contains a subunit (NFATp) which is present in unstimulated T cells and which forms a complex with Fos and Jun proteins in the nucleus of activated T cells9,11. Here we report that NFATp is a DNA-binding phosphoprotein of relative molecular mass ∼ 120,000 and is a substrate for Calcineurin in vitro. Purified NFATp forms DNA–protein complexes with recombinant Jun homodimers or Jun–Fos heterodimers; the DNA-binding domains of Fos and Jun are essential for the formation of the NFATp–Fos–Jun–DNA complex. The interaction between the lymphoid-specific factor NFATp and the ubiquitous transcription factors Fos and Jun provides a novel mechanism for combinatorial regulation of interleukin-2 gene transcription, which integrates the calcium-dependent and the protein-kinase C-dependent pathways of T-cell activation.
Leon J De Windt - One of the best experts on this subject based on the ideXlab platform.
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Modulatory Calcineurin-interacting proteins 1 and 2 function as Calcineurin facilitators in vivo.
Proceedings of the National Academy of Sciences, 2006Co-Authors: Bastiano Sanna, Leon J De Windt, Eric B. Brandt, Robert A. Kaiser, Paul T. Pfluger, Sandy A. Witt, Thomas R. Kimball, Eva Van Rooij, Marc E. Rothenberg, Matthias H. TschöpAbstract:The calcium-activated phosphatase Calcineurin is regulated by a binding cofactor known as modulatory Calcineurin-interacting protein (MCIP) in yeast up through mammals. The physiologic function of MCIP remains an area of ongoing investigation, because both positive and negative Calcineurin regulatory effects have been reported. Here we disrupted the mcip1 and mcip2 genes in the mouse and provide multiple lines of evidence that endogenous MCIP functions as a Calcineurin facilitator in vivo. Mouse embryonic fibroblasts deficient in both mcip1/2 showed impaired activation of nuclear factor of activated T cells (NFAT), suggesting that MCIP is required for efficient Calcineurin–NFAT coupling. Mice deficient in mcip1/2 showed a dramatic impairment in cardiac hypertrophy induced by pressure overload, neuroendocrine stimulation, or exercise, similar to mice lacking Calcineurin Aβ. Moreover, simultaneous deletion of Calcineurin Aβ in the mcip1/2-null background did not rescue impaired hypertrophic growth after pressure overload. Slow/oxidative fiber-type switching in skeletal muscle after exercise stimulation was also impaired in mcip1/2 mice, similar to Calcineurin Aβ-null mice. Moreover, CD4+ T cells from mcip1/2-null mice showed enhanced apoptosis that was further increased by loss of Calcineurin Aβ. Finally, mcip1/2-null mice displayed a neurologic phenotype that was similar to Calcineurin Aβ-null mice, such as increased locomotor activity and impaired working memory. Thus, a loss-of-function analysis suggests that MCIPs serve either a permissive or facilitative function for Calcineurin–NFAT signaling in vivo.
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Calcineurin promotes protein kinase c and c jun nh2 terminal kinase activation in the heart cross talk between cardiac hypertrophic signaling pathways
Journal of Biological Chemistry, 2000Co-Authors: Leon J De Windt, Thomas Force, Jeffery D. MolkentinAbstract:Abstract Multiple intracellular signaling pathways have been shown to regulate the hypertrophic growth of cardiomyocytes. Both necessary and sufficient roles have been described for the mitogen activated protein kinase1 (MAPK) signaling pathway, specific protein kinase C (PKC) isoforms, and Calcineurin. Here we investigate the interdependence between Calcineurin, MAPK, and PKC isoforms in regulating cardiomyocyte hypertrophy using three separate approaches. Hearts from hypertrophic Calcineurin transgenic mice were characterized for PKC and MAPK activation. Transgenic hearts demonstrated activation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2), but not p38 MAPK factors. Calcineurin transgenic hearts demonstrated increased activation of PKCα, β1, and θ, but not of e, β2, or λ. In a second approach, cultured cardiomyocytes were infected with a Calcineurin adenovirus to induce hypertrophy and the effects of pharmacologic inhibitors or co-infection with a dominant negative adenovirus were examined. Calcineurin-mediated hypertrophy was prevented with PKC inhibitors, Ca2+chelation, and attenuated with a dominant negative SEK-1 (MKK4) adenovirus, but inhibitors of ERK or p38 activation had no effect. In a third approach, we examined the activation of MAPK factors and PKC isoforms during the progression of load-induced hypertrophy in aortic banded rats with or without cyclosporine. We determined that inhibition of Calcineurin activity with cyclosporine prevented PKCα, θ, and JNK activation, but did not affect PKCe, β, λ, ERK1/2, or p38 activation. Collectively, these data indicate that Calcineurin hypertrophic signaling is interconnected with PKCα, θ, and JNK in the heart, while PKCe, β, λ, p38, and ERK1/2 are not involved in Calcineurin-mediated hypertrophy.
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targeted inhibition of Calcineurin prevents agonist induced cardiomyocyte hypertrophy
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Tyler Taigen, Leon J De Windt, Hae W Lim, Jeffery D. MolkentinAbstract:Cardiac hypertrophy is a major predictor of future morbidity and mortality. Recent investigation has centered around identifying the molecular signaling pathways that regulate cardiac myocyte reactivity with the goal of modulating pathologic hypertrophic programs. One potential regulator of cardiomyocyte hypertrophy is the calcium-sensitive phosphatase Calcineurin. We show here that Calcineurin enzymatic activity, mRNA, and protein levels are increased in cultured neonatal rat cardiomyocytes by hypertrophic agonists such as angiotensin II, phenylephrine, and 1% fetal bovine serum. This induction of Calcineurin activity was associated with an increase in Calcineurin Aβ (CnAβ) mRNA and protein, but not in CnAα or CnAγ. Agonist-dependent increases in Calcineurin enzymatic activity were specifically inhibited with an adenovirus expressing a noncompetitive peptide inhibitor of Calcineurin known as cain [Lai, M. M., Burnett, P. E., Wolosker, H., Blackshaw, S. & Snyder, S. H. (1998) J. Biol. Chem. 273, 18325–18331]. Targeted inhibition of Calcineurin with cain or an adenovirus expressing only the Calcineurin inhibitory domain of AKAP79 attenuated cardiomyocyte hypertrophy and atrial natriuretic factor expression in response to angiotensin II, phenylephrine, and 1% fetal bovine serum. These data demonstrate that Calcineurin is an important regulator of cardiomyocyte hypertrophy in response to certain agonists and suggest that cyclosporin A and FK506 function to attenuate cardiac hypertrophy by specifically inhibiting Calcineurin.