The RhoA/ROCK-I/MLC pathway is involved in the ethanol-induced apoptosis by anoikis in astrocytes
The RhoA/ROCK-I/MLC pathway is involved in the ethanol-induced apoptosis by anoikis in astrocytes
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DOI：
10.1242/jcs.02723
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发表时间：
2006-01-15
影响因子：
4
通讯作者：
Guerri, C
中科院分区：
文献类型：
--
作者：
Miñambres, R;Guasch, RM;Guerri, C
失巢凋亡是一种由锚定丧失引起的程序性细胞死亡，与组织稳态和疾病有关。乙醇是一种重要的致畸剂，可引起明显的中枢神经系统（CNS）功能障碍。在这里，我们表明，暴露于乙醇的星形胶质细胞发生形态学变化与失巢凋亡，包括周边重组的局灶性粘连和肌动蛋白-肌球蛋白系统，细胞收缩，膜起泡和染色质凝聚。我们发现，无论是小GTdR RhoA或其效应ROCK-I（Rho激酶），促进星形胶质细胞膜起泡。乙醇诱导ROCK-I活化，其由RhoA介导，而不是由半胱天冬酶-3裂解介导。因此，RhoA抑制剂C3完全消除了乙醇诱导的ROCK-I活化。此外，RhoA和ROCK的抑制防止乙醇诱导的膜起泡。乙醇还促进肌球蛋白轻链（MLC）磷酸化，这可能参与肌动蛋白-肌球蛋白收缩。所有这些发现都有力地支持了乙醇暴露的星形胶质细胞通过失巢凋亡进行凋亡，并且RhoA/ROCK-I/MLC通路参与了这一过程。
Anoikis is a programmed cell death induced by loss of anchorage that is involved in tissue homeostasis and disease. Ethanol is an important teratogen that induces marked central nervous system (CNS) dysfunctions. Here we show that astrocytes exposed to ethanol undergo morphological changes associated with anoikis, including the peripheral reorganization of both focal adhesions and actin-myosin system, cell contraction, membrane blebbing and chromatin condensation. We found that either the small GTPase RhoA or its effector ROCK-I (Rho kinase), promotes membrane blebbing in astrocytes. Ethanol induces a ROCK-I activation that is mediated by RhoA, rather than by caspase-3 cleavage. Accordingly, the RhoA inhibitor C3, completely abolishes the ethanol-induced ROCK-I activation. Furthermore, inhibition of both RhoA and ROCK prevents the membrane blebbing induced by ethanol. Ethanol also promotes myosin light chain (MLC) phosphorylation, which might be involved in the actin-myosin contraction. All of these findings strongly support that ethanol-exposed astrocytes undergo apoptosis by anoikis and also that the RhoA/ROCK-I/MLC pathway participates in this process.