Microtubule disruption and tumor suppression by mitogen-activated protein kinase phosphatase 4
Microtubule disruption and tumor suppression by mitogen-activated protein kinase phosphatase 4
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DOI：
10.1158/0008-5472.can-07-1968
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发表时间：
2007-11-15
期刊：
影响因子：
11.2
通讯作者：
Kulesz-Martin, Molly
中科院分区：
文献类型：
--
作者：
Liu, Yuangang;Lagowski, James;Kulesz-Martin, Molly
细胞外信号调节激酶 (Erk) 是 Ras 通路的下游效应器之一，其激活对于癌细胞的增殖和存活至关重要。 Erk 激活受到丝裂原激活蛋白激酶 (MAPK) 磷酸酶 (MKP) 的负向调节，而 MKP 通常会因 Erk 激活而上调，从而形成调节 Erk 活性的反馈回路。在寻找表皮癌变过程中 Ras 通路的早期改变时，我们鉴定了 MKP4，这是一种胞质 MKP，不仅对 Erk 具有特异性，而且在较小程度上对 c-jun-NH2-激酶和 p38 具有特异性。在缺乏 Ras 突变的表皮癌变克隆模型中，MKP4 在起始时下调，并在恶性转化时丢失。 MKP4 的缺失与鳞状细胞癌 (SCC) 有关，但与良性乳头状瘤克隆谱系无关，并且与小鼠皮肤中相对于良性肿瘤独立诱导的 SCC 相关。恶性肿瘤细胞中 MKP4 表达的重建导致细胞死亡和肿瘤抑制。与阻止细胞周期进入的 Erk 抑制不同，MKP4 重建导致 G(2)-M 相关的细胞死亡和微管破坏。因此，MKP4 破坏微管提供了一种通过胞质 MKP 抑制肿瘤的新机制，并意味着通过模拟 MKP4 功能的组合 MAPK 抑制来提供新的治疗策略。
The extracellular signal-regulated kinase (Erk) is one of the downstream effectors of the Ras pathway whose activation is essential for the proliferation and survival of cancer cells. Erk activation is negatively regulated by mitogen-activated protein kinase (MAPK) phosphatases (MKP), which are generally up-regulated by Erk activation, thus forming a feedback loop for regulation of Erk activity. In searching for early alterations in the Ras pathway in epidermal carcinogenesis, we identified MKP4, a cytosolic MKP with specificity to not only Erk, but also, to a lesser extent, c-jun-NH2-kinase and p38. MKP4 is down-regulated at initiation and lost at malignant conversion in a clonal model of epidermal carcinogenesis that lacks Ras mutation. The loss of MKP4 was associated with squamous cell carcinoma (SCC) but not benign papilloma clonal lineages and with independently induced SCC relative to benign tumors in mouse skin. Reconstitution of MKP4 expression in malignant tumor cells leads to cell death and tumor suppression. Unlike Erk inhibition that blocks cell cycle entry, MKP4 reconstitution resulted in G(2)-M associated cell death and microtubule disruption. Thus, microtubule disruption by MKP4 provides a novel mechanism for tumor suppression by a cytosolic MKP and implies a novel therapeutic strategy through combined MAPK inhibitions that mimic the function of MKP4.