Inhibition of HSP27 phosphorylation by a cell-permeant MAPKAP Kinase 2 inhibitor
Inhibition of HSP27 phosphorylation by a cell-permeant MAPKAP Kinase 2 inhibitor
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DOI：
10.1016/j.bbrc.2009.03.056
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发表时间：
2009-05-08
影响因子：
3.1
通讯作者：
Seal, Brandon L.
中科院分区：
文献类型：
--
作者：
Lopes, Luciana B.;Flynn, Charles;Seal, Brandon L.
热休克蛋白27（HSP 27）参与了许多细胞内信号传导过程。由于HSP 27的磷酸化可以调节其活性，因此抑制HSP 27磷酸化的能力可能具有临床相关性，特别是关于纤维化的治疗。我们已经开发了一种MAPKAP激酶2（MK2）的细胞渗透性肽抑制剂，MK2是一种磷酸化HSP 27的酶，通过将先前描述的MK2的肽底物与细胞穿透肽相结合。这种新的MK2抑制剂（MK2 i）在体外减少MK2对HSP 27的磷酸化。在10 μ M时，MK2 i抑制血清饥饿的人瘢痕疙瘩成纤维细胞中TGF-β 1诱导的HSP 27磷酸化。此外，10 μ M MK 2 i降低TGF-β 1诱导的结缔组织生长因子和I型胶原蛋白在血清饥饿的瘢痕疙瘩成纤维细胞内的表达。因此，MK2 i代表用于治疗纤维化病症的潜在治疗剂。(C)2009 Elsevier Inc. All rights reserved.
Heat shock protein 27 (HSP27) has been implicated in many intracellular signaling processes. Since the phosphorylation of HSP27 can modulate its activity, the ability to inhibit phosphorylation of HSP27 might have clinical relevance especially with regard to the treatment of fibrosis. We have developed a cell-permeant peptide inhibitor of MAPKAP Kinase 2 (MK2), an enzyme that phosphorylates HSP27, by combining a previously described peptide substrate of MK2 with a cell penetrating peptide. This novel MK2 inhibitor (MK2i) reduced HSP27 phosphorylation by MK2 in vitro. At 10 mu M, MK2i inhibited TGF-beta 1-induced HSP27 phosphorylation in serum-starved human keloid fibroblasts. In addition, 10 mu M MK2i decreased TGF-beta 1-induced expression of connective tissue growth factor and collagen type I within serum-starved keloid fibroblasts. Thus, MK2i represents a potential therapeutic for the treatment of fibrotic disorders. (C) 2009 Elsevier Inc. All rights reserved.