XMU-MP-1 is an inhibitor of the Hippo pathway kinases MST1/2 and has been shown to promote the downstream activation of the pro-proliferative, pro-regenerative and anti-apoptotic transcriptional regulator YAP1. We tested whether XMU-MP-1 can activate YAP1 in a model human mini-organ, namely the hair follicle, to determine whether it can be pharmacologically exploited to promote regeneration in the hair follicle as a novel strategy to treat pathological hair loss disorders. XMU-MP-1 treatment inhibited MOB1 phosphorylation but did not increase active YAP1 in the hair follicle. Rather than promote proliferation, XMU-MP-1 serendipitously decreased the number of Ki-67+, EdU+ and phospho histone H3+ hair matrix keratinocytes and antagonised the cytotoxic effects of paclitaxel. XMU-MP-1 perturbs epithelial cell cycle progression in a model human mini-organ. This may arise as an off-target effect, especially when XMU-MP-1 has been described to strongly inhibit 21 additional kinases beyond MST1/2. Therefore, whilst these effects may be dependent on tissue context, researchers should exercise caution when interpreting the effects of XMU-MP-1, especially in tissues with actively proliferating cell populations.

中文翻译：

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XMU-MP-1 在模型人类微型器官中诱导生长停滞并拮抗细胞周期依赖性紫杉醇细胞毒性

XMU-MP-1 是 Hippo 通路激酶 MST1/2 的抑制剂，已被证明可促进促增殖、促再生和抗凋亡转录调节因子 YAP1 的下游激活。我们测试了 XMU-MP-1 是否可以激活模型人类微型器官（即毛囊）中的 YAP1，以确定它是否可以在药理学上用于促进毛囊再生，作为治疗病理性脱发疾病的新策略。XMU-MP-1 处理抑制 MOB1 磷酸化，但不增加毛囊中的活性 YAP1。XMU-MP-1 非但没有促进增殖，反而意外地减少了 Ki-67+、EdU+ 和磷酸组蛋白 H3+ 毛基质角质形成细胞的数量，并拮抗了紫杉醇的细胞毒性作用。XMU-MP-1 扰乱模型人类微型器官中的上皮细胞周期进程。这可能是一种脱靶效应，尤其是当 XMU-MP-1 被描述为强烈抑制 MST1/2 之外的 21 种其他激酶时。因此，虽然这些影响可能取决于组织环境，但研究人员在解释 XMU-MP-1 的影响时应谨慎行事，特别是在具有活跃增殖细胞群的组织中。