Apoptosis Cancer and Development Laboratory, Lyon Cancer Research Center, Centre Léon Bérard, INSERM U1052-CNRS 5238, University of Lyon, 69008 Lyon, France.
Philos Trans R Soc Lond B Biol Sci. 2013 Mar 25;368(1617):20120075. doi: 10.1098/rstb.2012.0075. Print 2013 May 5.
Human HSP27 (HSPB1) is a molecular chaperone sensor which, through dynamic changes in its phosphorylation and oligomerization, allows cells to adapt to changes in their physiology and/or mount a protective response to injuries. In pathological conditions, the high level of HSPB1 expression can either be beneficial, such as in diseases characterized by cellular degenerations, or be malignant in cancer cells where it promotes tumourigenesis, metastasis and anti-cancer drug resistance. Structural changes allow HSPB1 to interact with specific client protein partners in order to modulate their folding/activity and/or half-life. Therefore, the search is open for therapeutic compounds aimed at either down- or upregulating HSPB1 activity. In this respect, we have previously described two peptide aptamers (PA11 and PA50) that specifically interact with HSPB1 small oligomers and decrease its anti-apoptotic and tumourigenic activities. A novel analysis of the different HSPB1-interacting aptamers that were isolated earlier revealed that one aptamer (PA23) has the intriguing ability to stimulate the protective activity of HSPB1. We show here that this aptamer abolishes the dominant negative effect induced by the R120G mutant of αB-crystallin (HSPB5) by disrupting its interaction with HSPB1. Hence, developing structure-based interfering strategies could lead to the discovery of HSPB1-based therapeutic drugs.
人类热休克蛋白 27（HSP27，HSPB1）是一种分子伴侣传感器，通过其磷酸化和寡聚化的动态变化，使细胞能够适应生理变化或对损伤做出保护反应。在病理条件下，HSPB1 的高表达水平既可以是有益的，如在以细胞退化为特征的疾病中，也可以是恶性的，如在促进肿瘤发生、转移和抗癌药物耐药性的癌细胞中。结构变化使 HSPB1 能够与特定的客户蛋白伴侣相互作用，以调节其折叠/活性和/或半衰期。因此，人们正在寻找旨在下调或上调 HSPB1 活性的治疗化合物。在这方面，我们之前描述了两种与 HSPB1 小寡聚物特异性相互作用的肽适体（PA11 和 PA50），并降低其抗凋亡和致瘤活性。对早期分离的不同 HSPB1 相互作用适体的新分析表明，一种适体（PA23）具有令人感兴趣的能力，可以刺激 HSPB1 的保护活性。我们在这里表明，这种适体通过破坏其与 HSPB1 的相互作用，消除了由 αB-晶状体蛋白（HSPB5）的 R120G 突变诱导的显性负效应。因此，开发基于结构的干扰策略可能会导致发现基于 HSPB1 的治疗药物。
