Ando Hideaki, Kawaai Katsuhiro, Bonneau Benjamin, Mikoshiba Katsuhiko
Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
Adv Biol Regul. 2018 May;68:64-76. doi: 10.1016/j.jbior.2017.12.001. Epub 2017 Dec 20.
The calcium ion (Ca) is a ubiquitous intracellular signaling molecule that regulates diverse physiological and pathological processes, including cancer. Increasing evidence indicates that oncogenes and tumor suppressors regulate the Ca transport systems. Inositol 1,4,5-trisphosphate (IP) receptors (IPRs) are IP-activated Ca release channels located on the endoplasmic reticulum (ER). They play pivotal roles in the regulation of cell death and survival by controlling Ca transfer from the ER to mitochondria through mitochondria-associated ER membranes (MAMs). Optimal levels of Ca mobilization to mitochondria are necessary for mitochondrial bioenergetics, whereas excessive Ca flux into mitochondria causes loss of mitochondrial membrane integrity and apoptotic cell death. In addition to well-known functions on outer mitochondrial membranes, B-cell lymphoma 2 (Bcl-2) family proteins are localized on the ER and regulate IPRs to control Ca transfer into mitochondria. Another regulatory protein of IPR, IPR-binding protein released with IP (IRBIT), cooperates with or counteracts the Bcl-2 family member depending on cellular states. Furthermore, several oncogenes and tumor suppressors, including Akt, K-Ras, phosphatase and tensin homolog (PTEN), promyelocytic leukemia protein (PML), BRCA1, and BRCA1 associated protein 1 (BAP1), are localized on the ER or at MAMs and negatively or positively regulate apoptotic cell death through interactions with IPRs and regulation of Ca dynamics. The remodeling of Ca signaling by oncogenes and tumor suppressors that interact with IPRs has fundamental roles in the pathology of cancers.
钙离子（Ca）是一种普遍存在的细胞内信号分子，可调节包括癌症在内的多种生理和病理过程。越来越多的证据表明，癌基因和肿瘤抑制因子可调节钙转运系统。肌醇1,4,5-三磷酸（IP）受体（IPRs）是位于内质网（ER）上的IP激活的钙释放通道。它们通过控制钙从内质网通过线粒体相关内质网膜（MAMs）转移到线粒体，在调节细胞死亡和存活中起关键作用。线粒体生物能量学需要向线粒体的最佳钙动员水平，而过多的钙流入线粒体则会导致线粒体膜完整性丧失和凋亡性细胞死亡。除了在线粒体外膜上的众所周知的功能外，B细胞淋巴瘤2（Bcl-2）家族蛋白还定位于内质网并调节IPRs以控制钙向线粒体的转移。IPR的另一种调节蛋白，即与IP一起释放的IPR结合蛋白（IRBIT），根据细胞状态与Bcl-2家族成员协同作用或相互拮抗。此外，包括Akt、K-Ras、磷酸酶和张力蛋白同源物（PTEN）、早幼粒细胞白血病蛋白（PML）、BRCA1和BRCA1相关蛋白1（BAP1）在内的几种癌基因和肿瘤抑制因子定位于内质网或MAMs，并通过与IPRs相互作用和调节钙动力学来负向或正向调节凋亡性细胞死亡。与IPRs相互作用的癌基因和肿瘤抑制因子对钙信号的重塑在癌症病理学中具有重要作用。
