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Cell Rep & Genes Dev研究发现:有丝分裂的新型调节子

来源:生物谷 2014-12-04 10:04

2014年12月4日 讯 /生物谷BIOON/ --近日,发表在国际杂志Genes & Development和Cell Reports上的两篇研究论文中,来自首尔大学的研究人员成功揭示了dsRNAs(双链RNA分子)和蛋白激酶R(PKR)调节哺乳动物细胞分裂的机制,相关研究或为理解肿瘤形成的过程提供一定的思路,同时研究者表示,研究成果也为理解抑制癌症发展及恶化的机体带来帮助。

文章中,研究者首次发现,在细胞有丝分裂期间,细胞中的dsRNAs会激活PKR,PKR是一种在病毒感染期间可以激活免疫反应的关键酶类;处于激活状态的PKR随后就会调节细胞中蛋白质的合成及调节有丝分裂的过程,而PKR激活的干扰则会引发有丝分裂因子的异常表达,从而使得有丝分裂进程减缓,最终导致细胞分裂缺失。

总的来讲,研究人员阐明了PKR调节细胞循环的新型作用,以及dsRNA可以作为一种信号传送器可以通过PKR在有丝分裂期间帮助传输信息。

接下来的研究中,研究者发现,有丝分裂期间PKR的激活可以被TAR RNA结合蛋白(TRBP)严格调控,而TRBP是PKR激活的一种抑制剂,该项研究工作就阐明,TRBP除了在microRNA生成过程中扮演的角色外,其还可通过调节PKR的激活来控制细胞循环。

最后研究者V. Narry Kim表示,这项研究将为理解免疫反应中的多种参与基因的功能带来一定的帮助,同时也为揭示dsRNAs在哺乳动物细胞分裂过程中的调节角色提供一定的线索,研究成果同时也为理解癌症的发生及开发新型靶向疗法提供希望。(生物谷Bioon.com)

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Deletion of Human tarbp2 Reveals Cellular MicroRNA Targets and Cell-Cycle Function of TRBP

Yoosik Kim3, Jinah Yeo3, Jung Hyun Lee3, Jun Cho, Daekwan Seo, Jong-Seo Kim, V. Narry Kim

TRBP functions as both a Dicer cofactor and a PKR inhibitor. However, the role of TRBP in microRNA (miRNA) biogenesis is controversial and its regulation of PKR in mitosis remains unexplored. Here, we generate TRBP knockout cells and find altered Dicer-processing sites in a subset of miRNAs but no effect on Dicer stability, miRNA abundance, or Argonaute loading. By generating PACT, another Dicer interactor, and TRBP/PACT double knockout (KO) cells, we further show that TRBP and PACT do not functionally compensate for one another and that only TRBP contributes to Dicer processing. We also report that TRBP is hyperphosphorylated by JNK in M phase when PKR is activated by cellular double-stranded RNAs (dsRNAs). Hyperphosphorylation potentiates the inhibitory activity of TRBP on PKR, suppressing PKR in M-G1 transition. By generating human TRBP KO cells, our study clarifies the role of TRBP and unveils negative feedback regulation of PKR through TRBP phosphorylation.

PKR is activated by cellular dsRNAs during mitosis and acts as a mitotic regulator

Yoosik Kim1,2, Jung Hyun Lee1,2, Jong-Eun Park1,2, Jun Cho1,2, Hyerim Yi1,2 and V. Narry Kim1,2,3

dsRNA-dependent protein kinase R (PKR) is a ubiquitously expressed enzyme well known for its roles in immune response. Upon binding to viral dsRNA, PKR undergoes autophosphorylation, and the phosphorylated PKR (pPKR) regulates translation and multiple signaling pathways in infected cells. Here, we found that PKR is activated in uninfected cells, specifically during mitosis, by binding to dsRNAs formed by inverted Alu repeats (IRAlus). While PKR and IRAlu-containing RNAs are segregated in the cytosol and nucleus of interphase cells, respectively, they interact during mitosis when nuclear structure is disrupted. Once phosphorylated, PKR suppresses global translation by phosphorylating the α subunit of eukaryotic initiation factor 2 (eIF2α). In addition, pPKR acts as an upstream kinase for c-Jun N-terminal kinase and regulates the levels of multiple mitotic factors such as CYCLINS A and B and POLO-LIKE KINASE 1 and phosphorylation of HISTONE H3. Disruption of PKR activation via RNAi or expression of a transdominant-negative mutant leads to misregulation of the mitotic factors, delay in mitotic progression, and defects in cytokinesis. Our study unveils a novel function of PKR and endogenous dsRNAs as signaling molecules during the mitosis of uninfected cells.

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