A conserved family of calcineurin regulators

TJ Kingsbury, KW Cunningham - Genes & development, 2000 - genesdev.cshlp.org
TJ Kingsbury, KW Cunningham
Genes & development, 2000genesdev.cshlp.org
The protein phosphatase calcineurin mediates many cellular responses to calcium signals.
Using a genetic screen in yeast, we identified a new family of proteins conserved in fungi
and animals that inhibit calcineurin function when overexpressed. Overexpression of the
yeast protein Rcn1p or the human homologs DSCR1 or ZAKI-4 inhibited two independent
functions of calcineurin in yeast: The activation of the transcription factor Tcn1p and the
inhibition of the H+/Ca2+ exchanger Vcx1p. Purified recombinant Rcn1p and DSCR1 bound …
The protein phosphatase calcineurin mediates many cellular responses to calcium signals. Using a genetic screen in yeast, we identified a new family of proteins conserved in fungi and animals that inhibit calcineurin function when overexpressed. Overexpression of the yeast protein Rcn1p or the human homologs DSCR1 or ZAKI-4 inhibited two independent functions of calcineurin in yeast: The activation of the transcription factor Tcn1p and the inhibition of the H+/Ca2+ exchanger Vcx1p. Purified recombinant Rcn1p and DSCR1 bound calcineurin in vitro and inhibited its protein phosphatase activity. Signaling via calmodulin, calcineurin, and Tcn1p induced Rcn1p expression, suggesting that Rcn1p operates as an endogenous feedback inhibitor of calcineurin. Surprisingly, rcn1 null mutants exhibited phenotypes similar to those of Rcn1p-overexpressing cells. This effect may be due to lower expression of calcineurin in rcn1 mutants during signaling conditions. Thus, Rcn1p levels may fine-tune calcineurin signaling in yeast. The structural and functional conservation between Rcn1p and DSCR1 suggests that the mammalian Rcn1p-related proteins, termed calcipressins, will modulate calcineurin signaling in humans and potentially contribute to disorders such as Down Syndrome.
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