Inhibition of SIRT2 in merlin/NF2-mutant Schwann cells triggers necrosis.
Inhibition of SIRT2 in merlin/NF2-mutant Schwann cells triggers necrosis.
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DOI：
10.18632/oncotarget.1422
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Fernández-Valle C
中科院分区：
文献类型：
--
作者：
Petrilli A;Bott M;Fernández-Valle C
NF2基因突变导致神经纤维瘤病2型（NF2），这是一种以神经系统中神经鞘瘤、脑膜瘤和室管膜瘤的发展为特征的疾病。Merlin是一种由NF 2基因编码的肿瘤抑制因子，可调节许多重要信号通路的活性。然而，尽管越来越多的知识梅林功能，有没有NF2药物治疗。在药理学活性化合物文库的中试高通量筛选中，我们测定了能够降低Nf2失活的小鼠雪旺细胞（MSC）活力的化合物作为人NF2雪旺细胞瘤的细胞模型。AGK2是SIRT2（sirtuin 2）抑制剂，被鉴定为候选化合物。SIRT2是七种哺乳动物sirtuins之一，是NAD+依赖性蛋白脱乙酰酶。我们发现merlin突变MSC比野生型对照MSC具有更高的SIRT2表达水平和更低的总赖氨酸乙酰化水平。SIRT 2的药理学抑制以剂量依赖性方式降低merlin突变MSC的活力，而不会大幅降低野生型MSC的活力。merlin突变MSC中SIRT2活性的抑制伴随着乳酸脱氢酶和高迁移率族蛋白1蛋白在没有显著凋亡、自噬或细胞周期停滞的情况下释放到培养基中。这些发现表明，SIRT2抑制触发merlin突变MSC的坏死，SIRT2是一个潜在的NF 2药物靶点。
Mutations in the NF2 gene cause Neurofibromatosis Type 2 (NF2), a disorder characterized by the development of schwannomas, meningiomas and ependymomas in the nervous system. Merlin, a tumor suppressor encoded by the NF2 gene, modulates activity of many essential signaling pathways. Yet despite increasing knowledge of merlin function, there are no NF2 drug therapies. In a pilot high-throughput screen of the Library of Pharmacologically Active Compounds, we assayed for compounds capable of reducing viability of mouse Schwann cells (MSC) with Nf2 inactivation as a cellular model for human NF2 schwannomas. AGK2, a SIRT2 (sirtuin 2) inhibitor, was identified as a candidate compound. SIRT2 is one of seven mammalian sirtuins that are NAD+ -dependent protein deacetylases. We show that merlin-mutant MSC have higher expression levels of SIRT2 and lower levels of overall lysine acetylation than wild-type control MSC. Pharmacological inhibition of SIRT2 decreases merlin-mutant MSC viability in a dose dependent manner without substantially reducing wild-type MSC viability. Inhibition of SIRT2 activity in merlin-mutant MSC is accompanied by release of lactate dehydrogenase and high mobility group box 1 protein into the medium in the absence of significant apoptosis, autophagy, or cell cycle arrest. These findings suggest that SIRT2 inhibition triggers necrosis of merlin-mutant MSCs and that SIRT2 is a potential NF2 drug target.
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影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
12.7
作者：
Kalamarides M;Acosta MT;Babovic-Vuksanovic D;Carpen O;Cichowski K;Evans DG;Giancotti F;Hanemann CO;Ingram D;Lloyd AC;Mayes DA;Messiaen L;Morrison H;North K;Packer R;Pan D;Stemmer-Rachamimov A;Upadhyaya M;Viskochil D;Wallace MR;Hunter-Schaedle K;Ratner N
通讯作者：
Ratner N
影响因子：
8.8
作者：
Chopra V;Quinti L;Kim J;Vollor L;Narayanan KL;Edgerly C;Cipicchio PM;Lauver MA;Choi SH;Silverman RB;Ferrante RJ;Hersch S;Kazantsev AG
通讯作者：
Kazantsev AG
影响因子：
2.6
作者：
Jacob, Abraham;Oblinger, Janet;Bush, Matthew L.;Brendel, Victoria;Santarelli, Griffin;Chaudhury, Abhik R.;Kulp, Samuel;La Perle, Krista M. D.;Chen, Ching-Shih;Chang, Long-Sheng;Welling, D. Bradley
通讯作者：
Welling, D. Bradley
影响因子：
3.5
作者：
Maxwell, Michele M.;Tomkinson, Elizabeth M.;Kazantsev, Aleksey G.
通讯作者：
Kazantsev, Aleksey G.