2,3,7,8-Tetrachlorodibenzo-p-dioxin and epidermal growth factor cooperatively suppress peroxisome proliferator-activated receptor-γ1 stimulation and restore focal adhesion complexes during adipogenesis:: Selective contributions of Src, Rho, and Erk distinguish these overlapping processes in C3H10T1/2 cells
2,3,7,8-Tetrachlorodibenzo-p-dioxin and epidermal growth factor cooperatively suppress peroxisome proliferator-activated receptor-γ1 stimulation and restore focal adhesion complexes during adipogenesis:: Selective contributions of Src, Rho, and Erk distinguish these overlapping processes in C3H10T1/2 cells
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DOI：
10.1124/mol.106.026534
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发表时间：
2006-12-01
影响因子：
3.6
通讯作者：
Jefcoate, Colin
中科院分区：
文献类型：
--
作者：
Liu, Xueqing;Jefcoate, Colin
地塞米松和3-异丁基-1-甲基黄嘌呤（DM）联合刺激多能C3 H10 T1/2细胞中的PPAR γ 1和脂肪生成，可被2，3，7，8-四氯二苯并二恶英（TCDD）（10 nM）抑制。这种抑制需要持续激活细胞外信号调节激酶（Erk）1/2。我们发现，它是由TCDD对表皮生长因子（EGF）信号的影响。DM启动细胞粘附的早期丧失，这被TCDD/EGF协同作用逆转。Src激酶活性对于粘附恢复、持续的Erk激活和过氧化物酶体增殖物激活受体（PPAR）γ 1的抑制是完全必要的。然而，MEK/Erk活性对TCDD诱导的粘附没有贡献。因此，粘附的刺激可能先于Erk的升高。通过α β整联蛋白与细胞外基质蛋白的相互作用以及随后的粘着斑激酶（FAK，Tyr 576/577）和桩蛋白（Tyr 118）的Src介导的磷酸化产生粘附。TCDD增强稳态Src介导的FAK磷酸化，但不桩蛋白。蛋白酪氨酸磷酸酶（PTPases）的抑制原钒酸盐（OVA）表明，这种Src活性是高度限制的PTPases。OVA部分抑制PTPases模拟TCDD产生EGF和Src依赖的细胞粘附和PPAR γ 1抑制作用。因此，TCDD可能诱导一种蛋白质，增强Src在粘附部位的有效性。Rho激酶（ROCK）抑制阻断了TCDD/EGF对聚集性粘着斑复合物的刺激，而不影响持续的Erk激活或抑制PPAR γ 1。因此，这种ROCK介导的整联蛋白复合物的聚集对于TCDD对Erk和PPARgamma 1的作用是不需要的。最小的胆固醇消耗与β-甲基环糊精衰减TCDD对PPAR γ 1和Erk激活的影响。因此，TCDD干预与细胞外蛋白有关。这表明，TCDD增强刺激EGF信号传导到Erk可能来自初始α β整合素复合物。
Stimulation of PPAR gamma 1 and adipogenesis in multipotential C3H10T1/2 cells by the combination of dexamethasone and 3-isobutyl-1-methylxanthine (DM) is suppressed by 2,3,7,8 tetrachlorodibenzodioxin (TCDD) (10 nM). This suppression requires sustained activation of extracellular signal-regulated kinase (Erk)1/2. We show that it arises from an effect of TCDD on epidermal growth factor (EGF) signaling. DM initiates an early loss of cell adhesion that is reversed by this TCDD/EGF synergy. Src kinase activity was completely essential for adhesion restoration, sustained Erk activation, and suppression of peroxisome proliferator-activated receptor (PPAR)gamma 1. MEK/Erk activity did not contribute, however, to TCDD-induced adhesion. Stimulation of adhesion may therefore precede elevation of Erk. Adhesion is produced by interaction of alpha beta integrins with extracellular matrix proteins and subsequent Src-mediated phosphorylation of focal adhesion kinase (FAK, Tyr576/577) and paxillin (Tyr118). TCDD enhanced the steady state Src-mediated phosphorylation of FAK but not of paxillin. Protein tyrosine phosphatase (PTPase) inhibition by orthovanadate (OVA) showed that this Src activity is highly restricted by PTPases. Partial inhibition of PTPases by OVA mimicked TCDD in producing EGF- and Src-dependent effects on cell adhesion and PPAR gamma 1 suppression. TCDD may therefore induce a protein that enhances Src effectiveness at adhesion sites. Rho kinase (ROCK) inhibition blocked TCDD/EGF stimulation of clustered focal adhesion complexes without affecting either sustained Erk activation or suppression of PPAR gamma 1. Thus, this ROCK-mediated clustering of integrin complexes is not needed for the effects of TCDD on Erk and PPAR gamma 1. A minimal cholesterol depletion with beta-methylcyclodextrin attenuated TCDD effects on PPAR gamma 1 and Erk activation. TCDD intervention is therefore linked to extracellular proteins. It indicates that TCDD-enhanced stimulation of EGF signaling to Erk may derive from the initial alpha beta integrin complexes.