Delayed Cell Cycle Progression in Selenoprotein W-depleted Cells Is Regulated by a Mitogen-activated Protein Kinase Kinase 4-p38/c-Jun NH2-terminal Kinase-p53 Pathway
Delayed Cell Cycle Progression in Selenoprotein W-depleted Cells Is Regulated by a Mitogen-activated Protein Kinase Kinase 4-p38/c-Jun NH2-terminal Kinase-p53 Pathway
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DOI：
10.1074/jbc.m112.346593
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发表时间：
2012-08-10
影响因子：
4.8
通讯作者：
Alkan, Zeynep
中科院分区：
文献类型：
--
作者：
Hawkes, Wayne Chris;Alkan, Zeynep
硒蛋白W （SEPW1）是一种普遍存在的高度保守的硫氧还蛋白样蛋白，其缺失会导致乳腺和前列腺上皮细胞中p53和p21（Cip1）依赖的瞬时G(1)期细胞周期停滞。SEPW1缺失增加了p53中Ser-33的磷酸化，这与p53泛素化降低和p53稳定有关。我们在这里报道延迟的细胞周期进程，Ser-33磷酸化，以及SEPW1缺失导致的p53核积累需要丝裂原活化蛋白激酶激酶4 （MKK4）。沉默MKK4可以挽救G(1)阻滞、Ser-33磷酸化和SEPW1缺失诱导的p53核积累，但沉默MKK3、MKK6或MKK7则没有。SEPW1沉默不改变MKK4的磷酸化状态，但增加了MKK4的总蛋白。沉默p38 gamma， p38 delta或JNK2部分地从SEPW1沉默中拯救了G(1)阻滞，这表明它们信号来自MKK4的下游。这些结果表明，SEPW1沉默增加了MKK4， MKK4激活p38 γ、p38 δ和JNK2磷酸化Ser-33上的p53，并导致短暂的G(1)阻滞。
Selenoprotein W (SEPW1) is a ubiquitous, highly conserved thioredoxin-like protein whose depletion causes a transient p53- and p21(Cip1)-dependent G(1)-phase cell cycle arrest in breast and prostate epithelial cells. SEPW1 depletion increases phosphorylation of Ser-33 in p53, which is associated with decreased p53 ubiquitination and stabilization of p53. We report here that delayed cell cycle progression, Ser-33 phosphorylation, and p53 nuclear accumulation from SEPW1 depletion require mitogen-activated protein kinase kinase 4 (MKK4). Silencing MKK4 rescued G(1) arrest, Ser-33 phosphorylation, and nuclear accumulation of p53 induced by SEPW1 depletion, but silencing MKK3, MKK6, or MKK7 did not. SEPW1 silencing did not change the phosphorylation state of MKK4 but increased total MKK4 protein. Silencing p38 gamma, p38 delta, or JNK2 partially rescued G(1) arrest from SEPW1 silencing, suggesting they signal downstream from MKK4. These results imply that SEPW1 silencing increases MKK4, which activates p38 gamma, p38 delta, and JNK2 to phosphorylate p53 on Ser-33 and cause a transient G(1) arrest.