分类: 生物学 >> 生物物理学 提交时间: 2016-05-12
摘要: RNA binding protein is identified as an important mediator of aberrant alternative splicing in muscle atrophy. The altered splicing of calcium channels, such as ryanodine receptors (RyRs), plays an important role in impaired excitation-contraction (E-C) coupling in muscle atrophy; however, the regulatory mechanisms of ryanodine receptor 1 (RyR1) alternative splicing leading to skeletal muscle atrophy remains to be investigated. In this study we demonstrated that CUG binding protein 1 (CUG-BP1) was up-regulated and the alternative splicing of RyR1 ASI (exon70) was aberrant during the process of neurogenic muscle atrophy both in human patients and mouse models. The gain and loss of function experiments in vivo demonstrated that altered splicing pattern of RyR1 ASI was directly mediated by an up-regulated CUG-BP1 function. Furthermore, we found that CUG-BP1 affected the calcium release activity in single myofibers and the extent of atrophy was significantly reduced upon gene silencing of CUG-BP1 in atrophic muscle. These findings improve our understanding of calcium signaling related biological function of CUG-BP1 in muscle atrophy. Thus, we provide an intriguing perspective of involvement of mis-regulated RyR1 splicing in muscular disease.
分类: 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学 提交时间: 2016-05-11
摘要: ERp44, an endoplasmic reticulum (ER) resident protein, regulates intracellular Ca2+ release and involves in the maturation of many proteins in mammalian cells. In this study, we investigated the effects and mechanism of ERp44 on cell apoptosis by using ERp44 knockdown stable HeLa cell lines. We found that ERp44 knockdown resulted in increases in cell apoptosis rate more than one fold higher than that of control; using serum starvation, caspase-3 protein level was significantly up-regulated in ERp44 knockdown cells compared to the control cells. Furthermore, we demonstrated that in response to serum starvation, the protein levels of CHOP and GRP78 were also largely raised in ERp44 knockdown cells. Moreover, caspase-12 was activated, which suggested cell apoptosis was induced by ER stress. Taken together, our results indicate that knockdown of ERp44 leads to cell apoptosis through the activation of ER stress. (C) 2015 Elsevier Inc. All rights reserved.