The RCN family of calcineurin regulators

Hilioti, Zoe; Cunningham, Kyle W.

doi:10.1016/s0006-291x(03)01515-8

Cited by 40 publications

(48 citation statements)

References 16 publications

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“…oti and Cunningham, 2003;Rothermel et al, 2003). These studies provide evidence that the regulatory effect of DSCR1 on calcineurin activity is dependent of the level of expression.…”

Section: Discussionmentioning

confidence: 60%

Restoration of DSCR1 to disomy in the trisomy 16 mouse model of Down syndrome does not correct cardiac or craniofacial development anomalies

Lange

Rothermel

Yutzey

2005

Developmental Dynamics

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The Down syndrome critical region 1 (DSCR1) gene is located in syntenic regions of human chromosome 21 and mouse chromosome 16 and encodes a regulatory protein in the calcineurin/NFAT pathway. DSCR1 expression in the embryonic brain, craniofacial structures, and heart is consistent with a role in contributing to Down syndrome developmental anomalies. In the trisomy 16 (Ts16) murine model of Down syndrome, expression of DSCR1 isoforms is elevated and NFAT transcriptional activity is decreased in the developing heart and brain. The individual contribution of DSCR1 to Down syndrome-related anomalies was examined by specific restoration of DSCR1 to disomic levels in Ts16 embryos. However, genetic restoration of DSCR1 did not rescue major morphological abnormalities in cardiac or craniofacial development. These data demonstrate that trisomy of DSCR1 alone does not significantly contribute to developmental defects in Ts16 mice and underscore the complexity of developmental anomalies associated with Down syndrome. Developmental Dynamics 233:954 -963, 2005.

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“…oti and Cunningham, 2003;Rothermel et al, 2003). These studies provide evidence that the regulatory effect of DSCR1 on calcineurin activity is dependent of the level of expression.…”

Section: Discussionmentioning

confidence: 60%

Restoration of DSCR1 to disomy in the trisomy 16 mouse model of Down syndrome does not correct cardiac or craniofacial development anomalies

Lange

Rothermel

Yutzey

2005

Developmental Dynamics

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“…However, recent evidence indicates that the functional regulation of the phosphatase can be quite complex. For instance, calcineurin activity can be regulated by members of the RCN (regulators of calcineurin) family, also termed calcipressins (32)(33)(34), represented in the budding yeast by the RCN1 gene (32). Most interestingly, the effect of Rcn1 on calcineurin activity depends on its phosphorylation state, and recent data points to Mck1, a member of the glycogen synthase kinase 3 family, as the major Rcn1 kinase in vivo (35).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Calcium-mediated Response to Alkaline Stress in Saccharomyces cerevisiae

Viladevall¹,

Serrano²,

Ruiz³

et al. 2004

Journal of Biological Chemistry

188

212

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Exposure of the yeast Saccharomyces cerevisiae to alkaline stress resulted in adaptive changes that involved remodeling the gene expression. Recent evidence suggested that the calcium-activated protein phosphatase calcineurin could play a role in alkaline stress signaling. By using an aequorin luminescence reporter, we showed that alkaline stress resulted in a sharp and transient rise in cytoplasmic calcium. This increase was largely abolished by addition of EGTA to the medium or in cells lacking Mid1 or Cch1, components of the high affinity cell membrane calcium channel. Under these circumstances, the alkaline response of different calcineurin-sensitive transcriptional promoters was also blocked. Therefore, exposure to alkali resulted in entry of calcium from the external medium, and this triggered a calcineurin-mediated response. The involvement of calcineurin and Crz1/Tcn1, the transcription factor activated by the phosphatase, in the transcriptional response triggered by alkalinization has been globally assessed by DNA microarray analysis in a time course experiment using calcineurin-deficient (cnb1) and crz1 mutants. We found that exposure to pH 8.0 increased at least 2-fold the mRNA levels of 266 genes. In many cases (60%) the response was rather early (peak after 10 min). The transcriptional response of 27 induced genes (10%) was reduced or fully abolished in cnb1 cells. In general, the response of crz1 mutants was similar to that of calcineurin-deficient cells. By analysis of a systematic deletion library, we found 48 genes whose mutation resulted in increased sensitivity to the calcineurin inhibitor FK506. Twenty of these mutations (42%) also provoked alkaline pH sensitivity. In conclusion, our results demonstrated that calcium signaling and calcineurin activation represented a significant component of the yeast response to environmental alkalinization.Calcium-mediated signaling mechanisms are used by virtually every eukaryotic cell to regulate a wide variety or cellular processes, including gene expression. Transient increases in cytosolic calcium results in activation of diverse enzymes, such as the protein phosphatase calcineurin. Calcineurin is a heterodimer of catalytic subunit and regulatory subunits. In the yeast Saccharomyces cerevisiae, the catalytic subunit is encoded by two genes, CNA1 and CNA2 (1), whereas a single gene, CNB1, encodes the regulatory subunit (2). Cells lacking the catalytic subunits, or the regulatory subunit, are deficient in calcineurin activity.Exposure of yeast cells to a number of signals, such as ␣-factor (3, 4), glucose (5), sphingosine (6), and certain stress conditions (7-9), triggers a rise in cytoplasmic calcium. This increase in calcium can be a consequence of external calcium influx or release from internal stores, such as the vacuole, and results in activation of calcineurin. For instance, hyperosmotic shock has been reported to provoke calcium release from vacuolar stores (8) through Yvc1, a member of the transient receptor potential channel family, and to trig...

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“…Rcn1p has a higher affinity for CN than Rcn2p (30). Whereas neither protein affected the control strain, overexpressing rcn2 (but not rcn1) rescued α-syn toxicity (Fig.…”

Section: Calcineurin Activation By Calmodulin Has Both Protective Andmentioning

confidence: 93%

Calcineurin determines toxic versus beneficial responses to α-synuclein

Caraveo

Auluck

Whitesell

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

105

144

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Calcineurin (CN) is a highly conserved Ca 2+ -calmodulin (CaM)-dependent phosphatase that senses Ca 2+ concentrations and transduces that information into cellular responses. Ca 2+ homeostasis is disrupted by α-synuclein (α-syn), a small lipid binding protein whose misfolding and accumulation is a pathological hallmark of several neurodegenerative diseases. We report that α-syn, from yeast to neurons, leads to sustained highly elevated levels of cytoplasmic Ca 2+ , thereby activating a CaM-CN cascade that engages substrates that result in toxicity. Surprisingly, complete inhibition of CN also results in toxicity. Limiting the availability of CaM shifts CN's spectrum of substrates toward protective pathways. Modulating CN or CN's substrates with highly selective genetic and pharmacological tools (FK506) does the same. FK506 crosses the blood brain barrier, is well tolerated in humans, and is active in neurons and glia. Thus, a tunable response to CN, which has been conserved for a billion years, can be targeted to rebalance the phosphatase's activities from toxic toward beneficial substrates. These findings have immediate therapeutic implications for synucleinopathies.

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The RCN family of calcineurin regulators

Cited by 40 publications

References 16 publications

Restoration of DSCR1 to disomy in the trisomy 16 mouse model of Down syndrome does not correct cardiac or craniofacial development anomalies

Restoration of DSCR1 to disomy in the trisomy 16 mouse model of Down syndrome does not correct cardiac or craniofacial development anomalies

Characterization of the Calcium-mediated Response to Alkaline Stress in Saccharomyces cerevisiae

Calcineurin determines toxic versus beneficial responses to α-synuclein

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