Calcineurin is essential in cyclosporin A- and FK506-sensitive yeast strains.

Breuder, T.; Hemenway, Charles S.; Movva, N. Rao; Cárdenas, María E.; Heitman, Joseph

doi:10.1073/pnas.91.12.5372

Cited by 141 publications

(151 citation statements)

References 43 publications

(79 reference statements)

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“…CN function can be eliminated by deleting the regulatory subunit cnb1 alone or by the combined deletion of the catalytic subunits cna1 and cna2. As expected (29), neither manipulation affected the growth of the control strain ( Fig deleting CN eliminated BSCaM IQ protection (Fig. S4B).…”

Section: Calcineurin Activation By Calmodulin Has Both Protective Andmentioning

confidence: 54%

“…Importantly, FK506 provides a means to continuously vary CN inhibition over a very broad range. FK506 inhibits CN by precisely the same mechanism in yeast and in mammals (29,31) although higher concentrations of this drug are required in yeast than in mammalian cells (Materials and Methods). Consistent with our hypothesis, in the HiTox strain intermediate concentrations of FK506 protected against α-syn toxicity, whereas higher concentrations eliminated this protection (Fig.…”

Section: Calcineurin Activation By Calmodulin Has Both Protective Andmentioning

confidence: 99%

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Calcineurin determines toxic versus beneficial responses to α-synuclein

Caraveo

Auluck

Whitesell

et al. 2014

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

104

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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Section: Calcineurin Activation By Calmodulin Has Both Protective Andmentioning

confidence: 54%

Section: Calcineurin Activation By Calmodulin Has Both Protective Andmentioning

confidence: 99%

Calcineurin determines toxic versus beneficial responses to α-synuclein

Caraveo

Auluck

Whitesell

et al. 2014

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

104

144

View full text Add to dashboard Cite

show abstract

“…However, these mutant strains exhibit growth defects and result in petite cells (36). Furthermore, the expression of the mutant proteins varied.…”

Section: Vid22pmentioning

confidence: 99%

Cyclophilin A Mediates Vid22p Function in the Import of Fructose-1,6-bisphosphatase into Vid Vesicles

Brown

Cui

Hung

et al. 2001

Journal of Biological Chemistry

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“…This hypothesis is analogous to the mechanisms of cytotoxicity of FK506 and rapamycin. FK506 forms a complex with highly conserved prolylisomerase immunophilin FKBP12, which in turn targets calcineurin, a Ca 2ϩ -calmodulin-regulated serine/threoninespecific protein phosphatase (8,38,39). Calcineneurin has been reported as a conserved target of the FK506-FKBP12 complex from yeast and T-cells of human to pathogenic fungi (40).…”

Section: Noncovalent But Strong Binding Of Hwy 289 and Hwy 336 To Wismentioning

confidence: 99%

Selective Inhibition of MAPKK Wis1 in the Stress-activated MAPK Cascade of Schizosaccharomyces pombe by Novel Berberine Derivatives

Jang

Jwa

Kim

et al. 2002

Journal of Biological Chemistry

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Berberine alkaloids supposedly have diverse biological effects including anti-tumor activity in mice, anti-Candida activity, cytotoxic activities against human cancer cell lines, and inhibition of dopamine biosynthesis (1-4); however, their cytotoxic targets and biological mechanisms have yet to be identified. Since berberine has been shown to inhibit the growth of Candida albicans, Candida glabrata, and Candida tropicalis, 515 synthetic and semisynthetic berberine derivatives were produced and screened for more effective anti-fungal activity in C. albicans (5). C. albicans is the most frequently isolated fungal pathogen in humans. Its ability to change from a yeast form to a filamentous hypal or pseudohypal form during growth is thought to contribute to its virulence (6). HWY 289 and HWY 336 were selected because of their highly effective anti-Candida properties in the screen. Since C. albicans is a diploid fungus with no known sexual cycle and target validation by genetic approaches is limited, direct targets of HWY 289 and HWY 336 were identified in the fission yeast Schizosaccharomyces pombe, which is amenable for genetic studies. Studies using various mutations of the budding yeast S. cerevisiae have shown that yeast provides a good system for identifying targets of known compounds such as rapamycin and FK506 (7,8). Recently, the usage of budding yeast Saccharomyces cerevisiae has been expanded to include screenings for valuable chemical compounds or peptides for anticancer drugs and protein kinase inhibitors (9 -12). In this paper, we report that the novel berberine derivatives having anti-Candida properties, HWY 289 and HWY 336, selectively inhibit the in vivo and in vitro activities of a specific kinase in the stress-activated mitogen-activated protein kinase (MAPK) 1 cascade in S. pombe. MAPK (sometimes called extracellular signal-regulated kinase (ERK)) cascades are highly conserved signaling cassettes found in all eukaryotes. Eukaryotic cells respond to diverse extracellular stimuli such as growth factors, hormones, high temperature, osmotic shock, and hydroxyl radicals by activating distinct MAP kinase cascades, which lead to diverse regulatory events including proliferation, differentiation, and cell death. Therefore, kinases in distinct MAPK cascades serve as effective cytotoxic targets for a number of anti-fungal, antitumor, and anti-inflammatory drugs. Each MAPK cascade is composed of a series of three or more protein kinases, each phosphorylating, thereby activating, the next kinase in the pathway. MAPKs are activated by phosphorylation at conserved threonine and tyrosine residues in the catalytic domain by MAPK kinases (MAPKKs, sometimes called MEKs). These are in turn activated by phosphorylation of specific conserved serine/threonine residues by MAPK kinase kinases (MAPKKKs, sometimes called MEKKs). Several MAPK cascades exist in a cell. Each of them functions in parallel by mediating

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Calcineurin is essential in cyclosporin A- and FK506-sensitive yeast strains.

Abstract: The muophmmunOSUPPrat complexes cydophilin-cyclosporin A (CsA) and FKBP12-FK506inhibit the phosphatase calcneurin to block T-cell activation.

Cited by 141 publications

References 43 publications

Calcineurin determines toxic versus beneficial responses to α-synuclein

Calcineurin determines toxic versus beneficial responses to α-synuclein

Cyclophilin A Mediates Vid22p Function in the Import of Fructose-1,6-bisphosphatase into Vid Vesicles

Selective Inhibition of MAPKK Wis1 in the Stress-activated MAPK Cascade of Schizosaccharomyces pombe by Novel Berberine Derivatives

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