LIM-domain protein cysteine- and glycine-rich protein 2 (CRP2) is a novel marker of hepatic stellate cells and binding partner of the protein inhibitor of activated STAT1.
LIM-domain protein cysteine- and glycine-rich protein 2 (CRP2) is a novel marker of hepatic stellate cells and binding partner of the protein inhibitor of activated STAT1.
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DOI：
10.1042/0264-6021:3590485
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发表时间：
2001-11
期刊：
影响因子：
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通讯作者：
Ralf Weiskirchen;Markus Moser;S. Weiskirchen;Martin Erdel;Sandra Dahmen;Reinhard Buettner;Axel M. Gressner
中科院分区：
文献类型：
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作者：
Ralf Weiskirchen;Markus Moser;S. Weiskirchen;Martin Erdel;Sandra Dahmen;Reinhard Buettner;Axel M. Gressner
肝星状细胞的激活被认为是肝纤维化发展的主要步骤，其特征是富含维生素A的静止细胞转变为增殖性、纤维化和收缩性肌成纤维细胞。早期细胞激活和转分化过程中调控基因的鉴定对于扩展我们对肝纤维发生的了解至关重要。在肝脏中，CSRP2 基因仅由星状细胞表达，而在肝细胞、肝窦内皮细胞或库普弗细胞中检测不到转录本。血小板源性生长因子诱导的星状细胞的早期激活伴随着 CSRP2 表达的增强。在转分化的后期阶段，这些细胞中 CSRP2 的表达在体外和体内均受到抑制。 CSRP2 编码的富含半胱氨酸和甘氨酸的双 LIM 结构域蛋白 (CRP)2 被认为充当分子接头，将两个或多个尚未鉴定的蛋白质成分排列成大分子复合物。为了鉴定这些蛋白质并赋予 CRP2 细胞功能，在酵母双杂交筛选中以全长 CRP2 作为诱饵筛选人类 cDNA 文库。激活的 STAT1 的蛋白抑制剂（“PIAS1”）被证明可以选择性地与 CRP2 的 C 端 LIM 结构域结合。通过共聚焦激光扫描显微镜和共免疫沉淀分析的共定位实验证实了两种蛋白质在细胞环境中的物理相互作用。这些结果表明 CRP2 是 JAK/STAT 信号通路中潜在的新因子，并表明 CSRP2 的抑制可能是肝星状细胞肌纤维母细胞转变的先决条件。
Activation of hepatic stellate cells is considered to be the main step in the development of liver fibrosis, which is characterized by the transition of quiescent vitamin-A-rich cells to proliferative, fibrogenic and contractile myofibroblasts. The identification of regulatory genes during early cell activation and transdifferentiation is essential to extend our knowledge of hepatic fibrogenesis. In liver, the gene CSRP2 is exclusively expressed by stellate cells, whereas no transcripts are detectable in hepatocytes, sinusoidal endothelial cells or Kupffer cells. The early activation of stellate cells induced by platelet-derived growth factor is accompanied by an enhanced expression of CSRP2. During later stages of transdifferentiation, the expression of CSRP2 in these cells is suppressed in vitro and in vivo. The CSRP2-encoded cysteine- and glycine-rich double-LIM-domain protein (CRP)2 is proposed to function as a molecular adapter, arranging two or more as yet unidentified protein constituents into a macromolecular complex. To identify these proteins and assign a cellular function to CRP2, a human cDNA library was screened with full-length CRP2 as bait in a yeast two-hybrid screen. The protein inhibitor of activated STAT1 ('PIAS1') was shown to associate selectively with the C-terminal LIM domain of CRP2. Physical interaction of both proteins in the cellular environment was confirmed by co-localization experiments with confocal laser scanning microscopy and co-immunoprecipitation analysis. These results establish CRP2 as a potential new factor in the JAK/STAT-signalling pathway and suggest that the suppression of CSRP2 might be a prerequisite for the myofibroblastic transition of hepatic stellate cells.