由RSK介导的C/EBPβ磷酸化产生了一个对细胞存活至关重要的功能性XEXD半胱天冬酶抑制盒。
C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival.
作者信息
Buck M, Poli V, Hunter T, Chojkier M
机构信息
Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
出版信息
Mol Cell. 2001 Oct;8(4):807-16. doi: 10.1016/s1097-2765(01)00374-4.
Upon activation by liver injury, hepatic stellate cells produce excessive fibrous tissue leading to cirrhosis. The hepatotoxin CCl(4) induced activation of RSK, phosphorylation of C/EBPbeta on Thr(217), and proliferation of stellate cells in normal mice, but caused apoptosis of these cells in C/EBPbeta-/- or C/EBPbeta-Ala(217) (a dominant-negative nonphosphorylatable mutant) transgenic mice. Both C/EBPbeta-PThr(217) and the phosphorylation mimic C/EBPbeta-Glu(217), but not C/EBPbeta-Ala(217), were associated with procaspases 1 and 8 in vivo and in vitro and inhibited their activation. Our data suggest that C/EBPbeta phosphorylation on Thr(217) creates a functional XEXD caspase substrate/inhibitor box (K-Phospho-T(217)VD) that is mimicked by C/EBPbeta-Glu(217) (KE(217)VD). C/EBPbeta-/- and C/EBPbeta-Ala(217) stellate cells were rescued from apoptosis by the cell permeant KE(217)VD tetrapeptide or C/EBPbeta-Glu(217).
在受到肝损伤激活后，肝星状细胞会产生过多纤维组织，导致肝硬化。肝毒素四氯化碳（CCl₄）可诱导正常小鼠的核糖体S6激酶（RSK）激活、C/EBPβ在苏氨酸217（Thr(217)）位点磷酸化以及星状细胞增殖，但在C/EBPβ基因敲除小鼠或C/EBPβ-Ala(217)（一种显性负性不可磷酸化突变体）转基因小鼠中却导致这些细胞凋亡。在体内和体外，C/EBPβ-PThr(217)以及磷酸化模拟物C/EBPβ-Glu(217)，而非C/EBPβ-Ala(217)，均与procaspases 1和8相关联并抑制它们的激活。我们的数据表明，C/EBPβ在Thr(217)位点的磷酸化产生了一个功能性的XEXD半胱天冬酶底物/抑制剂盒（K-磷酸化-T(217)VD），C/EBPβ-Glu(217)（KE(217)VD）可模拟该盒。通过细胞穿透性KE(217)VD四肽或C/EBPβ-Glu(217)可使C/EBPβ基因敲除和C/EBPβ-Ala(217)星状细胞免于凋亡。
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