Akl Haidar, Bultynck Geert
Department Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Biochim Biophys Acta. 2013 Apr;1835(2):180-93. doi: 10.1016/j.bbcan.2012.12.001. Epub 2012 Dec 8.
Proto-oncogenes and tumor suppressors critically control cell-fate decisions like cell survival, adaptation and death. These processes are regulated by Ca(2+) signals arising from the endoplasmic reticulum, which at distinct sites is in close proximity to the mitochondria. These organelles are linked by different mechanisms, including Ca(2+)-transport mechanisms involving the inositol 1,4,5-trisphosphate receptor (IP3R) and the voltage-dependent anion channel (VDAC). The amount of Ca(2+) transfer from the endoplasmic reticulum to mitochondria determines the susceptibility of cells to apoptotic stimuli. Suppressing the transfer of Ca(2+) from the endoplasmic reticulum to the mitochondria increases the apoptotic resistance of cells and may decrease the cellular responsiveness to apoptotic signaling in response to cellular damage or alterations. This can result in the survival, growth and proliferation of cells with oncogenic features. Clearly, proper maintenance of endoplasmic reticulum Ca(2+) homeostasis and dynamics including its links with the mitochondrial network is essential to detect and eliminate altered cells with oncogenic features through the apoptotic pathway. Proto-oncogenes and tumor suppressors exploit the central role of Ca(2+) signaling by targeting the IP3R. There are an increasing number of reports showing that activation of proto-oncogenes or inactivation of tumor suppressors directly affects IP3R function and endoplasmic reticulum Ca(2+) homeostasis, thereby decreasing mitochondrial Ca(2+) uptake and mitochondrial outer membrane permeabilization. In this review, we provide an overview of the current knowledge on the proto-oncogenes and tumor suppressors identified as IP3R-regulatory proteins and how they affect endoplasmic reticulum Ca(2+) homeostasis and dynamics.
原癌基因和肿瘤抑制因子对细胞命运决定起着关键控制作用，如细胞存活、适应和死亡。这些过程由内质网产生的Ca(2+)信号调节，内质网在不同部位与线粒体紧密相邻。这些细胞器通过不同机制相连，包括涉及肌醇1,4,5 -三磷酸受体（IP3R）和电压依赖性阴离子通道（VDAC）的Ca(2+)转运机制。从内质网到线粒体的Ca(2+)转移量决定了细胞对凋亡刺激的敏感性。抑制Ca(2+)从内质网向线粒体的转移可增加细胞的凋亡抗性，并可能降低细胞对细胞损伤或改变所引发的凋亡信号的反应性。这可能导致具有致癌特征的细胞存活、生长和增殖。显然，内质网Ca(2+)稳态和动力学的适当维持，包括其与线粒体网络的联系，对于通过凋亡途径检测和消除具有致癌特征的异常细胞至关重要。原癌基因和肿瘤抑制因子通过靶向IP3R发挥Ca(2+)信号的核心作用。越来越多的报告表明，原癌基因的激活或肿瘤抑制因子的失活直接影响IP3R功能和内质网Ca(2+)稳态，从而减少线粒体Ca(2+)摄取和线粒体外膜通透性。在本综述中，我们概述了目前关于被鉴定为IP3R调节蛋白的原癌基因和肿瘤抑制因子的知识，以及它们如何影响内质网Ca(2+)稳态和动力学。
