Modulatory calcineurin-interacting proteins 1 and 2 function as calcineurin facilitatorsin vivo

Abstract

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 mcip1͞2 showed impaired activation of nuclear factor of activated T cells (NFAT), suggesting that MCIP is required for efficient calcineurin-NFAT coupling. Mice deficient in mcip1͞2 showed a dramatic impairment in cardiac hypertrophy induced by pressure overload, neuroendocrine stimulation, or exercise, similar to mice lacking calcineurin A␤. Moreover, simultaneous deletion of calcineurin A␤ in the mcip1͞2-null background did not rescue impaired hypertrophic growth after pressure overload. Slow͞oxidative fiber-type switching in skeletal muscle after exercise stimulation was also impaired in mcip1͞2 mice, similar to calcineurin A␤-null mice. Moreover, CD4 ؉ T cells from mcip1͞2-null mice showed enhanced apoptosis that was further increased by loss of calcineurin A␤. Finally, mcip1͞2-null mice displayed a neurologic phenotype that was similar to calcineurin A␤-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.heart ͉ PP2B ͉ signal transduction

Down Syndrome Critical Region-1 Is a Transcriptional Target of Nuclear Factor of Activated T Cells-c1 within the Endocardium during Heart Development

“…The negative feedback loop may serve to maintain endocardial NFATc1 protein function at a stable level during heart valve morphogenesis. However, mice lacking DSCR1 and/or DSCR1-like 1 survive to adulthood with no apparent severe defects in cardiac morphogenesis (31). These findings may suggest the presence of redundant pathways that compensate for the loss of function of DSCR1.…”

The RCAN carboxyl end mediates calcineurin docking-dependent inhibition via a site that dictates binding to substrates and regulators

“…The evidence in these studies comes mostly from overexpression of RCANs, but the CN-inhibitory potential of these proteins is also shown in some mouse models of Rcan1 loss of function (19)(20)(21)(22). However, the phenotypes of null mutants of Saccharomyces cerevisiae Rcn1p (23) and Rcan1 Ϫ/Ϫ or Rcan2 Ϫ/Ϫ mice (19,24) are compatible with reduced CN activity, which has led to suggestions of a positive action of RCANs on CN. The 3 human RCANs (RCAN1, RCAN2, and RCAN3) have a high amino acid identity in the central and C-terminal regions (12).…”

Down Syndrome Expressed Protein; DSCR-1 Deters Cancer and Septic Inflammation

“…The phenotype exhibited by the DSCR-1 whole gene knockout mice shows exacerbated constitutively active calcineurin-dependent cardiac hypertrophy, whereas cardiac hypertrophy in response to pressure overload and chronic adrenergic stimulation was blunted in these mice (Vega et al, 2003). In addition, double knockout mice of DSCR-1 and modulator of calcineurin interacting protein (MCIP) 2 also resulted in calcineurin facilitation, although it is difficult to distinguish the relative contribution between DSCR-1 and MCIP2 in these events (Sanna et al, 2006). It light of previous results and the results presented here suggesting differing expression patterns and functions of the DSCR-1s and 1L isoforms, it is plausible that the phenotype of the DSCR-1 null mice results from the complex deletion of both DSCR-1L and DSCR-1s isoforms.…”