科研之友
微信
新浪微博
Facebook
分享链接
摘要
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 mcip1/2 showed impaired activation of nuclear factor of activated T cells (NEAT), suggesting that MCIP is required for efficient calcineurin-NFAT coupling. Mice deficient in mcip1/2 showed a dramatic impairment in cardiac hypertrophy induced by pressure overload, neuroendocrine stimulation, or exercise, similar to mice lacking calcineurin A beta. Moreover, simultaneous deletion of calcineurin A beta in the mcip1/2-null background did not rescue impaired hypertrophic growth after pressure overload. Slow/oxidative fiber-type switching in skeletal muscle after exercise stimulation was also impaired in mcip1/2 mice, similar to calcineurin A beta-null mice. Moreover, CD4(+) T cells from mcip1 /2-null mice showed enhanced apoptosis that was further increased by loss of calcineurin A beta. Finally, mcip1/2-null mice displayed a neurologic phenotype that was similar to calcineurin A beta-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-NEAT signaling in vivo.
- 出版日期2006-5-9
