The role of p70S6K in hepatic stellate cell collagen gene expression and cell proliferation
The role of p70S6K in hepatic stellate cell collagen gene expression and cell proliferation
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DOI：
10.1074/jbc.m409444200
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发表时间：
2005-04-08
影响因子：
4.8
通讯作者：
Rippe, RA
中科院分区：
文献类型：
--
作者：
Gäbele, E;Reif, S;Rippe, RA
在肝纤维化过程中，肝星状细胞（HSC）经历了一个复杂的激活过程，其特征是增殖增加和细胞外基质沉积。70-kDa核糖体S6激酶（p70（S6 K））被有丝分裂原、生长因子和激素以磷脂酰肌醇3-激酶依赖性方式激活。p70（S6 K）调节蛋白质合成、增殖和细胞周期控制。由于这些过程参与了HSC的活化，我们研究了p70（S6 K）在HSC增殖、细胞周期控制和I型胶原表达中的作用。血小板衍生生长因子（PDGF）刺激p70（S6 K）磷酸化，这是由磷脂酰肌醇3-激酶抑制剂LY 294002阻断。雷帕霉素阻断了p70（S6 K）的磷酸化，但对PDGF诱导的Akt磷酸化没有影响，将p70（S6 K）定位在Akt的下游。抑制HSC增殖的转化生长因子-β不影响PDGF诱导的p70（S6 K）磷酸化。雷帕霉素处理不影响α 1（I）胶原mRNA，但减少I型胶原蛋白的分泌。平滑肌α-肌动蛋白的表达不受雷帕霉素治疗的影响，表明HSC活化没有改变。雷帕霉素抑制血清诱导的DNA合成约2倍。此外，雷帕霉素降低细胞周期蛋白D1、D3和E的表达，但不降低细胞周期蛋白D2、Rb-Ser（780）和Rb-Ser（795）的表达。总之，p70（S6 K）在HSC增殖、胶原蛋白表达和细胞周期控制中起着至关重要的作用，因此代表了肝纤维化的潜在治疗靶点。
During fibrosis the hepatic stellate cell (HSC) undergoes a complex activation process characterized by increased proliferation and extracellular matrix deposition. The 70-kDa ribosomal S6 kinase (p70(S6K)) is activated by mitogens, growth factors, and hormones in a phosphatidylinositol 3-kinase-dependent manner. p70(S6K) regulates protein synthesis, proliferation, and cell cycle control. Because these processes are involved in HSC activation, we investigated the role of p70(S6K) in HSC proliferation, cell cycle control, and type I collagen expression. Platelet-derived growth factor ( PDGF) stimulated p70(S6K) phosphorylation, which was blocked by LY294002, an inhibitor of phosphatidylinositol 3-kinase. Rapamycin blocked phosphorylation of p70(S6K) but had no affect on PDGF-induced Akt phosphorylation, positioning p70(S6K) downstream of Akt. Transforming growth factor-beta, which inhibits HSC proliferation, did not affect PDGF-induced p70(S6K) phosphorylation. Rapamycin treatment did not affect alpha 1(I) collagen mRNA but reduced type I collagen protein secretion. Expression of smooth muscle alpha-actin was not affected by rapamycin treatment, indicating that HSC activation was not altered. Rapamycin inhibited serum-induced DNA synthesis similar to 2-fold. Moreover, rapamycin decreased expression of cyclins D1, D3, and E but not cyclin D2, Rb-Ser(780), and Rb-Ser(795). Together, p70(S6K) plays a crucial role in HSC proliferation, collagen expression, and cell cycle control, thus representing a potential therapeutic target for liver fibrosis.