H11/HspB8 and Its Herpes Simplex Virus Type 2 Homologue ICP10PK Share Functions That Regulate Cell Life/Death Decisions and Human Disease.
H11/HspB8 and Its Herpes Simplex Virus Type 2 Homologue ICP10PK Share Functions That Regulate Cell Life/Death Decisions and Human Disease.
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DOI：
10.1155/2012/395329
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发表时间：
2012
影响因子：
4
通讯作者：
Lee KS
中科院分区：
文献类型：
--
作者：
Aurelian L;Laing JM;Lee KS
小分子热休克蛋白又称热休克蛋白B，是一个广泛表达的蛋白大家族，含有一个90个残基的结构域，称为α-晶体蛋白。在这里，我们主要关注家族成员H11/HspB8及其单纯疱疹病毒2型(HSV-2)同源基因ICP10PK，并讨论这种关系对人类疾病可能产生的影响。H11/HspB8和ICP10PK是非典型的蛋白激酶。它们共享多种功能活动，包括信号、未折叠蛋白反应(UPR)和生命周期潜力的调节。在黑素细胞中，H11/HspB8会导致生长停滞。在高比例的黑色素瘤、前列腺癌、尤文氏肉瘤和血液系统恶性肿瘤中，它通过异常的DNA甲基化而被沉默。在异种移植模型中，H11/HspB8的恢复表达诱导细胞死亡和抑制肿瘤生长，证明H11/HspB8是一种肿瘤抑制因子。这一功能涉及多种不同的死亡途径的激活，所有这些途径都始于H11/HspB8介导的转化生长因子β激活的激酶1的磷酸化。ICP10PK和H11/HspB8均参与炎症过程，通过Toll样受体依赖的途径激活树突状细胞，并可能参与自身免疫的发生。讨论了H11/HspB8与ICP10PK的潜在进化关系、对人类疾病的影响以及治疗策略的发展。
Small heat shock proteins (sHsp) also known as HspB are a large family of widely expressed proteins that contain a 90 residues domain known as α-crystallin. Here, we focus on the family member H11/HspB8 and its herpes simplex virus type 2 (HSV-2) homologue ICP10PK, and discuss the possible impact of this relationship on human disease. H11/HspB8 and ICP10PK are atypical protein kinases. They share multi-functional activity that encompasses signaling, unfolded protein response (UPR) and the regulation of life cycle potential. In melanocytes H11/HspB8 causes growth arrest. It is silenced in a high proportion of melanoma prostate cancer, Ewing's sarcoma and hematologic malignancies through aberrant DNA methylation. Its restored expression induces cell death and inhibits tumor growth in xenograft models, identifying H11/HspB8 as a tumor suppressor. This function involves the activation of multiple and distinct death pathways, all of which initiate with H11/HspB8-mediated phosphorylation of transforming growth factor β-activated kinase 1 (TAK1). Both ICP10PK and H11/HspB8 were implicated in inflammatory processes that involve dendritic cells activation through Toll-like receptor-dependent pathways and may contribute to the onset of autoimmunity. The potential evolutionary relationship of H11/HspB8 to ICP10PK, its impact on human disorders and the development of therapeutic strategies are discussed.