Dysregulated Raf/MEK/extracellular signal-regulated kinase (ERK) signaling, a common hallmark of tumorigenesis, can trigger innate tumor-suppressive mechanisms, which must be inactivated for carcinogenesis to occur. This innate tumor-suppressive signaling may provide a potential therapeutic target. Here we report that mortalin (HSPA9/GRP75/PBP74) is a novel negative regulator of Raf/MEK/ERK and may provide a target for the reactivation of tumor-suppressive signaling of the pathway in cancer. We found that mortalin is present in the MEK1/MEK2 proteome and is upregulated in human melanoma biopsy specimens. In different MEK/ERK-activated cancer cell lines, mortalin depletion induced cell death and growth arrest, which was accompanied by increased p21(CIP1) transcription and MEK/ERK activity. Remarkably, MEK/ERK activity was necessary for mortalin depletion to induce p21(CIP1) expression in B-Raf(V600E)-transformed cancer cells regardless of their p53 status. In contrast, in cell types exhibiting normal MEK/ERK status, mortalin overexpression suppressed B-Raf(V600E)- or ΔRaf-1:ER-induced MEK/ERK activation, p21(CIP1) expression, and cell cycle arrest. Other HSP70 family chaperones could not effectively replace mortalin for p21(CIP1) regulation, suggesting a unique role for mortalin. These findings reveal a novel mechanism underlying p21(CIP1) regulation in MEK/ERK-activated cancer and identify mortalin as a molecular switch that mediates the tumor-suppressive versus oncogenic result of dysregulated Raf/MEK/ERK signaling. Our study also demonstrates that p21(CIP1) has dual effects under mortalin-depleted conditions, i.e., mediating cell cycle arrest while limiting cell death.

译文

:Raf / MEK /细胞外信号调节激酶(ERK)信号失调,是肿瘤发生的常见标志,可以触发固有的肿瘤抑制机制,必须将其抑制才能发生癌变。这种先天性的肿瘤抑制信号传导可能会提供潜在的治疗靶点。在这里我们报告,mortalin(HSPA9 / GRP75 / PBP74)是Raf / MEK / ERK的新型负调节剂,可能为癌症通路中抑癌信号的重新激活提供目标。我们发现,mortalin存在于MEK1 / MEK2蛋白质组中,并在人类黑素瘤活检标本中上调。在不同的MEK / ERK激活的癌细胞系中,凡尔林耗竭诱导细胞死亡和生长停滞,并伴随着p21(CIP1)转录和MEK / ERK活性的增加。值得注意的是,MEK / ERK活性对于在B-Raf(V600E)转化的癌细胞中诱导p21(CIP1)表达的人乳清蛋白耗尽是必需的,而与p53的状态无关。相反,在表现出正常MEK / ERK状态的细胞类型中,mortalin过表达抑制了B-Raf(V600E)-或ΔRaf-1:ER诱导的MEK / ERK活化,p21(CIP1)表达和细胞周期停滞。其他HSP70家族分子伴侣不能有效替代p21(CIP1)调节中的mortalin,这提示了mortalin的独特作用。这些发现揭示了MEK / ERK激活的癌症中p21(CIP1)调节的基础的新机制,并确定了mortalin作为介导Raf / MEK / ERK信号失调的肿瘤抑制和致癌结果的分子开关。我们的研究还表明,p21(CIP1)在耗尽凡尔林的条件下具有双重作用,即在限制细胞死亡的同时介导细胞周期停滞。

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