Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Allele-Specific Phenotype Suggests a Possible Stimulatory Activity of RCAN-1 on Calcineurin in Caenorhabditis elegans

  • Li, Weixun (Department of Life Science, Hanyang University) ;
  • Choi, Tae-Woo (Department of Life Science, Hanyang University) ;
  • Ahnn, Joohong (Department of Life Science, Hanyang University) ;
  • Lee, Sun-Kyung (Department of Life Science, Hanyang University)
  • Received : 2016.09.13
  • Accepted : 2016.10.31
  • Published : 2016.11.30
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Abstract

Regulator of calcineurin 1 (RCAN1) binds to calcineurin through the PxIxIT motif, which is evolutionarily conserved. SP repeat phosphorylation in RCAN1 is required for its complete function. The specific interaction between RCAN1 and calcineurin is critical for calcium/calmodulin-dependent regulation of calcineurin serine/threonine phosphatase activity. In this study, we investigated two available deletion rcan-1 mutants in Caenorhabditis elegans, which proceed differently for transcription and translation. We found that rcan-1 may be required for calcineurin activity and possess calcineurin-independent function in body growth and egg-laying behavior. In the genetic background of enhanced calcineurin activity, the rcan-1 mutant expressing a truncated RCAN-1 which retains the calcineurin-binding PxIxIT motif but misses SP repeats stimulated growth, while rcan-1 lack mutant resulted in hyperactive egg-laying suppression. These data suggest rcan-1 has unknown functions independent of calcineurin, and may be a stimulatory calcineurin regulator under certain circumstances.

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References

  1. Aramburu, J., Garcia-Cozar, F., Raghavan, A., Okamura, H., Rao, A., and Hogan, P.G. (1998). Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT. Mol. Cell 1, 627-637. https://doi.org/10.1016/S1097-2765(00)80063-5
  2. Bandyopadhyay, J., Lee, J., Lee, J., Lee, J.I., Yu, J.R., Jee, C., Cho, J.H., Jung, S., Lee, M.H., Zannoni, S., et al. (2002). Calcineurin, a calcium/calmodulin-dependent protein phosphatase, is involved in movement, fertility, egg laying, and growth in Caenorhabditis elegans. Mol. Biol. Cell 13, 3281-3293. https://doi.org/10.1091/mbc.E02-01-0005
  3. Chang, K.T., and Min, K.T. (2009). Upregulation of three Drosophila homologs of human chromosome 21 genes alters synaptic function: implications for Down syndrome. Proc. Natl. Acad. Sci. USA 106, 17117-17122. https://doi.org/10.1073/pnas.0904397106
  4. Chang, K.T., Shi, Y.J., and Min, K.T. (2003). The Drosophila homolog of Down's syndrome critical region 1 gene regulates learning: implications for mental retardation. Proc. Natl. Acad. Sci. USA 100, 15794-15799. https://doi.org/10.1073/pnas.2536696100
  5. Crawford, D.R., Leahy, K.P., Abramova, N., Lan, L., Wang, Y., and Davies, K.J. (1997). Hamster adapt78 mRNA is a Down syndrome critical region homologue that is inducible by oxidative stress. Arch. Biochem. Biophys. 342, 6-12. https://doi.org/10.1006/abbi.1997.0109
  6. Dierssen, M., Arque, G., McDonald, J., Andreu, N., Martinez-Cue, C., Florez, J., and Fillat, C. (2011). Behavioral characterization of a mouse model overexpressing DSCR1/ RCAN1. PLoS One 6, e17010. https://doi.org/10.1371/journal.pone.0017010
  7. Ermak, G., Morgan, T.E., and Davies, K.J. (2001). Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease. J. Biol. Chem. 276, 38787-38794. https://doi.org/10.1074/jbc.M102829200
  8. Fuentes, J.J., Pritchard, M.A., Planas, A.M., Bosch, A., Ferrer, I., and Estivill, X. (1995). A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum. Mol. Genet. 4, 1935-1944. https://doi.org/10.1093/hmg/4.10.1935
  9. Fuentes, J.J., Pritchard, M.A., and Estivill, X. (1997). Genomic organization, alternative splicing, and expression patterns of the DSCR1 (Down syndrome candidate region 1) gene. Genomics 44, 358-361. https://doi.org/10.1006/geno.1997.4866
  10. Fuentes, J.J., Genesca, L., Kingsbury, T.J., Cunningham, K.W., Perez-Riba, M., Estivill, X., and de la Luna, S. (2000). DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurinmediated signaling pathways. Hum. Mol. Genet. 9, 1681-1690. https://doi.org/10.1093/hmg/9.11.1681
  11. Genesca, L., Aubareda, A., Fuentes, J.J., Estivill, X., De La Luna, S., and Perez-Riba, M. (2003). Phosphorylation of calcipressin 1 increases its ability to inhibit calcineurin and decreases calcipressin half-life. Biochem. J. 374, 567-575. https://doi.org/10.1042/bj20030267
  12. Gorlach, J., Fox, D.S., Cutler, N.S., Cox, G.M., Perfect, J.R., and Heitman, J. (2000). Identification and characterization of a highly conserved calcineurin binding protein, CBP1/calcipressin, in Cryptococcus neoformans. EMBO J. 19, 3618-3629. https://doi.org/10.1093/emboj/19.14.3618
  13. Hilioti, Z., Gallagher, D.A., Low-Nam, S.T., Ramaswamy, P., Gajer, P., Kingsbury, T.J., Birchwood, C.J., Levchenko, A., and Cunningham, K.W. (2004). GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs. Genes Dev. 18, 35-47. https://doi.org/10.1101/gad.1159204
  14. Hoeffer, C.A., Dey, A., Sachan, N., Wong, H., Patterson, R.J., Shelton, J.M., Richardson, J.A., Klann, E., and Rothermel, B.A. (2007). The Down syndrome critical region protein RCAN1 regulates long-term potentiation and memory via inhibition of phosphatase signaling. J. Neurosci. 27, 13161-13172. https://doi.org/10.1523/JNEUROSCI.3974-07.2007
  15. Keating, D.J., Dubach, D., Zanin, M.P., Yu, Y., Martin, K., Zhao, Y.F., Chen, C., Porta, S., Arbones, M.L., Mittaz, L., et al. (2008). DSCR1/RCAN1 regulates vesicle exocytosis and fusion pore kinetics: implications for Down syndrome and Alzheimer's disease. Hum. Mol. Genet. 17, 1020-1030. https://doi.org/10.1093/hmg/ddm374
  16. Kingsbury, T.J., and Cunningham, K.W. (2000). A conserved family of calcineurin regulators. Genes Dev. 14, 1595-1604.
  17. Kishi, T., Ikeda, A., Nagao, R., and Koyama, N. (2007). The SCFCdc4 ubiquitin ligase regulates calcineurin signaling through degradation of phosphorylated Rcn1, an inhibitor of calcineurin. Proc. Natl. Acad. Sci. USA 104, 17418-17423. https://doi.org/10.1073/pnas.0704951104
  18. Kuhara, A., Inada, H., Katsura, I., and Mori, I. (2002). Negative regulation and gain control of sensory neurons by the C. elegans calcineurin TAX-6. Neuron 33, 751-763. https://doi.org/10.1016/S0896-6273(02)00607-4
  19. Kurabayashi, N., and Sanada, K. (2013). Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells. Genes Dev. 27, 2708-2721. https://doi.org/10.1101/gad.226381.113
  20. Lee, J.I., Dhakal, B.K., Lee, J., Bandyopadhyay, J., Jeong, S.Y., Eom, S.H., Kim, D.H., and Ahnn, J. (2003). The Caenorhabditis elegans homologue of down syndrome critical region 1, RCN-1, inhibits multiple functions of the phosphatase calcineurin. J. Mol. Biol. 328, 147-156. https://doi.org/10.1016/S0022-2836(03)00237-7
  21. Li, W., Bell, H.W., Ahnn, J., and Lee, S.K. (2015). Regulator of Calcineurin (RCAN-1) Regulates Thermotaxis Behavior in Caenorhabditis elegans. J. Mol. Biol. 427, 3457-3468. https://doi.org/10.1016/j.jmb.2015.07.017
  22. Martin, K.R., Corlett, A., Dubach, D., Mustafa, T., Coleman, H.A., Parkington, H.C., Merson, T.D., Bourne, J.A., Porta, S., Arbones, M.L., et al. (2012). Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory. Hum. Mol. Genet. 21, 3025-3041. https://doi.org/10.1093/hmg/dds134
  23. Mehta, S., Li, H., Hogan, P.G., and Cunningham, K.W. (2009). Domain architecture of the regulators of calcineurin (RCANs). and identification of a divergent RCAN in yeast. Mol. Cell. Biol. 29, 2777-2793. https://doi.org/10.1128/MCB.01197-08
  24. Park, B.J., Lee, J., II, Lee, J., Kim, S., Choi, K.Y., Park, C.S., and Ahnn, J. (2001a). Isolation of deletion mutants by reverse genetics incaenorhabditis elegans. Korean J. Biol. Sci. 5, 65-69. https://doi.org/10.1080/12265071.2001.9647584
  25. Park, B.J., Lee, D.G., Yu, J.R., Jung, S.K., Choi, K., Lee, J., Lee, J., Kim, Y.S., Lee, J.I., Kwon, J.Y., et al. (2001b). Calreticulin, a calcium-binding molecular chaperone, is required for stress response and fertility in Caenorhabditis elegans. Mol. Biol. Cell 12, 2835-2845. https://doi.org/10.1091/mbc.12.9.2835
  26. Reynolds, L.E., Watson, A.R., Baker, M., Jones, T.A., D'Amico, G., Robinson, S.D., Joffre, C., Garrido-Urbani, S., Rodriguez-Manzaneque, J.C., Martino-Echarri, E., et al. (2010). Tumour angiogenesis is reduced in the Tc1 mouse model of Down's syndrome. Nature 465, 813-817. https://doi.org/10.1038/nature09106
  27. Trent, C., Tsuing, N., and Horvitz, H.R. (1983). Egg-laying defective mutants of the nematode Caenorhabditis elegans. Genetics 104, 619-647.
  28. Wang, W., Zhu, J.Z., Chang, K.T., and Min, K.T. (2012). DSCR1 interacts with FMRP and is required for spine morphogenesis and local protein synthesis. EMBO J. 31, 3655-3666. https://doi.org/10.1038/emboj.2012.190
  29. Wang, W., Rai, A., Hur, E.M., Smilansky, Z., Chang, K.T., and Min, K.T. (2016). DSCR1 is required for both axonal growth cone extension and steering. J. Cell Biol. 213, 451-462. https://doi.org/10.1083/jcb.201510107
  30. Wiese, A.G., Pacifici, R.E., and Davies, K.J. (1995). Transient adaptation of oxidative stress in mammalian cells. Arch. Biochem. Biophys. 318, 231-240. https://doi.org/10.1006/abbi.1995.1225
  31. Yang, J., Rothermel, B., Vega, R.B., Frey, N., McKinsey, T.A., Olson, E.N., Bassel-Duby, R., and Williams, R.S. (2000). Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ. Res. 87, E61-68. https://doi.org/10.1161/01.RES.87.12.e61

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