Novel pro-survival functions of the Kruppel-like transcription factor Egr2 in promotion of macrophage colony-stimulating factor-mediated osteoclast survival downstream of the MEK/ERK pathway
Novel pro-survival functions of the Kruppel-like transcription factor Egr2 in promotion of macrophage colony-stimulating factor-mediated osteoclast survival downstream of the MEK/ERK pathway
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DOI：
10.1074/jbc.m709500200
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发表时间：
2008-03-21
影响因子：
4.8
通讯作者：
Oursler, Merry J.
中科院分区：
文献类型：
--
作者：
Bradley, Elizabeth W.;Ruan, Ming M.;Oursler, Merry J.
确定巨噬细胞集落刺激因子（M-CSF）介导的破骨细胞存活的潜在机制可能对确定治疗过度骨丢失的新方法很重要。本研究探讨了M-CSF介导的MEK/ERK激活，并确定了该途径的下游效应。M-CSF激活MEK/ERK并诱导立即早期基因Egr 2的MEK依赖性表达。抑制MEK 1/2或抑制Egr 2增加破骨细胞凋亡。相反，野生型Egr 2或不能结合内源性阻遏物Nab 1/2（caEgr 2）的Egr 2点突变体抑制基础破骨细胞凋亡并从由MEK 1/2或Egr 2抑制诱导的凋亡中拯救破骨细胞。机制上，Egr 2诱导促生存Blc 2家族成员Mcl 1，同时刺激蛋白酶体介导的促凋亡Bim的降解。此外，Egr 2增加了c-Cbl的表达，c-Cbl是催化Bim泛素化的E3泛素连接酶。因此，M-CSF通过Egr 2的MEK/ERK依赖性诱导来控制Mcl 1/Bim比率，从而促进破骨细胞存活，证明了Egr 2在促进存活中的新功能。
Determining the underlying mechanisms of macrophage colony-stimulating factor (M-CSF)-mediated osteoclast survival may be important in identifying novel approaches for treating excessive bone loss. This study investigates M-CSF-mediated MEK/ERK activation and identifies a downstream effector of this pathway. M-CSF activates MEK/ERK and induces MEK-dependent expression of the immediate early gene Egr2. Inhibition of either MEK1/2 or inhibition of Egr2 increases osteoclast apoptosis. In contrast, wild-type Egr2 or an Egr2 point mutant unable to bind the endogenous repressors Nab1/2 (caEgr2) suppresses basal osteoclast apoptosis and rescues osteoclasts from apoptosis induced by MEK1/2 or Egr2 inhibition. Mechanistically, Egr2 induces pro-survival Blc2 family member Mcl1 while stimulating proteasome-mediated degradation of pro-apoptotic Bim. In addition, Egr2 increased the expression of c-Cbl, the E3 ubiquitin ligase that catalyzes Bim ubiquitination. M-CSF, therefore, promotes osteoclast survival through MEK/ ERK-dependent induction of Egr2 to control the Mcl1/Bim ratio, documenting a novel function of Egr2 in promoting survival.