Mitogen-Activated Protein Kinase-Interacting Kinase Regulates mTOR/AKT Signaling and Controls the Serine/Arginine-Rich Protein Kinase-Responsive Type 1 Internal Ribosome Entry Site-Mediated Translation and Viral Oncolysis
Mitogen-Activated Protein Kinase-Interacting Kinase Regulates mTOR/AKT Signaling and Controls the Serine/Arginine-Rich Protein Kinase-Responsive Type 1 Internal Ribosome Entry Site-Mediated Translation and Viral Oncolysis
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DOI：
10.1128/jvi.01884-14
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发表时间：
2014-11-01
影响因子：
5.4
通讯作者：
Gromeier, Matthias
中科院分区：
文献类型：
--
作者：
Brown, Michael C.;Dobrikov, Mikhail I.;Gromeier, Matthias
翻译机制是主要有丝分裂信号网络的主要接受者，包括Raf-ERK1/2和磷酸肌醇3-激酶(PI3K)-雷帕霉素（mTOR）的机制靶点。小核糖核酸病毒内核糖体进入位点（IRES）介导的翻译和细胞致病作用易受宿主细胞中此类信号级联状态的影响。我们确定肿瘤特异性细胞毒性的脊髓灰质炎病毒/鼻病毒嵌合体PVSRIPO由Raf-ERK1/2信号促进增殖作用蛋白激酶(MAPK)交互激酶(MNK)及其影响的分区/活动Ser / Arg (SR)丰富的蛋白激酶(SRPK) (M . c .布朗,j·d·科比,e . y . Dobrikova M . Shveygert s s Bradrick诉Chandramohan d·d·Bigner和M, Gromeier, j .微生物学报。22:13135 - 13148,2014年,doi: http://dx.doi.org/10.1128/JVI.01883-14)。我们发现MNK通过mTOR和AKT调控SRPK。我们的研究揭示了mnk控制的作用于mTORC2-AKT的机制。由此产生的AKT信号的抑制减弱了SRPK活性，从而增强了1型小核糖核酸病毒IRES的翻译，并有利于PVSRIPO肿瘤细胞的毒性和杀伤。PVSRIPO是一种含有人鼻病毒2型（HRV2） IRES的1型减毒脊髓灰质炎病毒（PV） （Sabin）疫苗，其溶瘤免疫疗法在复发性胶质母细胞瘤（GBM）的肿瘤内输注的临床试验中显示出早期的前景。我们的研究表明PVSRIPO的核心机制原理，肿瘤选择性翻译和细胞毒性，依赖于组成型ERK1/2-MNK信号，这些信号抵消了恶性肿瘤中AKT-SRPK活性失控的有害影响。
Translation machinery is a major recipient of the principal mitogenic signaling networks involving Raf-ERK1/2 and phosphoinositol 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR). Picornavirus internal ribosomal entry site (IRES)-mediated translation and cytopathogenic effects are susceptible to the status of such signaling cascades in host cells. We determined that tumor-specific cytotoxicity of the poliovirus/rhinovirus chimera PVSRIPO is facilitated by Raf-ERK1/2 signals to the mitogen-activated protein kinase (MAPK)-interacting kinase (MNK) and its effects on the partitioning/activity of the Ser/Arg (SR)-rich protein kinase (SRPK) (M. C. Brown, J. D. Bryant, E. Y. Dobrikova, M. Shveygert, S. S. Bradrick, V. Chandramohan, D. D. Bigner, and M, Gromeier, J. Virol. 22:13135-13148, 2014, doi:http://dx.doi.org/10.1128/JVI.01883-14). Here, we show that MNK regulates SRPK via mTOR and AKT. Our investigations revealed a MNK-controlled mechanism acting on mTORC2-AKT. The resulting suppression of AKT signaling attenuates SRPK activity to enhance picornavirus type 1 IRES translation and favor PVSRIPO tumor cell toxicity and killing.IMPORTANCEOncolytic immunotherapy with PVSRIPO, the type 1 live-attenuated poliovirus (PV) (Sabin) vaccine containing a human rhinovirus type 2 (HRV2) IRES, is demonstrating early promise in clinical trials with intratumoral infusion in recurrent glioblastoma (GBM). Our investigations demonstrate that the core mechanistic principle of PVSRIPO, tumor-selective translation and cytotoxicity, relies on constitutive ERK1/2-MNK signals that counteract the deleterious effects of runaway AKT-SRPK activity in malignancy.