Deletion of the Dual Specific Phosphatase-4 (DUSP-4) Gene Reveals an Essential Non-redundant Role for MAP Kinase Phosphatase-2 (MKP-2) in Proliferation and Cell Survival
Deletion of the Dual Specific Phosphatase-4 (DUSP-4) Gene Reveals an Essential Non-redundant Role for MAP Kinase Phosphatase-2 (MKP-2) in Proliferation and Cell Survival
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DOI：
10.1074/jbc.m110.181370
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发表时间：
2011-04-15
影响因子：
4.8
通讯作者：
Plevin, Robin
中科院分区：
文献类型：
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作者：
Lawan, Ahmed;Al-Harthi, Sameer;Plevin, Robin
丝裂原激活蛋白激酶磷酸酶-2 (MKP-2) 是一种 1 型核双特异性磷酸酶 (DUSP)，与多种癌症有关。我们研究了 MKP-2 在来自新型 MKP-2 (DUSP-4) 缺失小鼠的小鼠胚胎成纤维细胞 (MEF) 中 MAP 激酶磷酸化、细胞增殖和存活反应的调节作用。我们发现血清和PDGF在野生型MET中诱导ERK依赖性MKP-2表达，但在MKP-2(-/-) MEF中不诱导表达。 PDGF 对持续 ERK 磷酸化的刺激在 MKP-2(-/-) MEF 中增强，而茴香霉素诱导的 JNK 仅略有增加。然而，观察到对细胞生长参数的显着影响。 MKP-2(-/-) MEF 中的细胞增殖率显着降低，并与细胞倍增时间显着增加相关。腺病毒 MKP-2 感染逆转了增殖的减少。细胞周期分析揭示了与细胞周期蛋白 B 积累和 cdc2 磷酸化增强相关的 G(2)/M 相转变受阻。当用茴香霉素刺激时，来自 MKP-2(-/-) 小鼠的 MEF 也显示出细胞凋亡增强，这与 caspase-3 裂解和 γ H2AX 磷酸化增加相关。腺病毒 MKP-2 感染可逆转细胞凋亡的增加，并与 JNK 信号传导的选择性抑制相关。总的来说，这些数据首次证明 MKP-2 在调节细胞周期进程和细胞凋亡中具有关键的非冗余作用。
Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP) implicated in a number of cancers. We examined the role of MKP-2 in the regulation of MAP kinase phosphorylation, cell proliferation, and survival responses in mouse embryonic fibroblasts (MEFs) derived from a novel MKP-2 (DUSP-4) deletion mouse. We show that serum and PDGF induced ERK-dependent MKP-2 expression in wild type METs but not in MKP-2(-/-) MEFs. PDGF stimulation of sustained ERK phosphorylation was enhanced in MKP-2(-/-) MEFs, whereas anisomycin-induced JNK was only marginally increased. However, marked effects upon cell growth parameters were observed. Cellular proliferation rates were significantly reduced in MKP-2(-/-) MEFs and associated with a significant increase in cell doubling time. Infection with adenoviral MKP-2 reversed the decrease in proliferation. Cell cycle analysis revealed a block in G(2)/M phase transition associated with cyclin B accumulation and enhanced cdc2 phosphorylation. MEFs from MKP-2(-/-) mice also showed enhanced apoptosis when stimulated with anisomycin correlated with increased caspase-3 cleavage and gamma H2AX phosphorylation. Increased apoptosis was reversed by adenoviral MKP-2 infection and correlated with selective inhibition of JNK signaling. Collectively, these data demonstrate for the first time a critical non-redundant role fir MKP-2 in regulating cell cycle progression and apoptosis.