Phosphatidylinositol 3-kinase mediates mitogen-induced human airway smooth muscle cell proliferation.
Phosphatidylinositol 3-kinase mediates mitogen-induced human airway smooth muscle cell proliferation.
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磷脂酰肌醇 3-激酶介导丝裂原诱导的人气道平滑肌细胞增殖。
DOI：
10.1152/ajplung.1999.277.1.l65
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
PanettieriJr,RA
中科院分区：
文献类型：
--
作者：
Krymskaya,VP;Penn,RB;Orsini,MJ;Scott,PH;Plevin,RJ;Walker,TR;Eszterhas,AJ;Amrani,Y;Chilvers,ER;PanettieriJr,RA
气道平滑肌肥大和增生是慢性重症哮喘气流阻塞的重要病理特征。尽管进行了大量的研究工作，但调节ASM生长的细胞机制仍不清楚。最近的证据表明，丝裂原诱导的磷脂酰肌醇(PI)特异性磷脂酶C(PLC)的激活和PI依赖的钙动员既不足以也不必要刺激人ASM的增殖。在这项研究中，我们发现磷脂酰肌醇(PtdIns)3-激酶是人类ASM增殖的关键调节因子。PtdIns 3-激酶抑制剂Wortmannin和LY-294002可显著降低凝血酶和表皮生长因子诱导的DNA合成(IC50分别为∼10 nM和∼3μM)。在单独的实验中，Wortmannin和LY-294002显著抑制由表皮生长因子和凝血酶刺激的人ASM细胞诱导的PtdIns3-K和70-kDa S6蛋白激酶(Pp70S6k)的激活，但对表皮生长因子和凝血酶诱导的p42/p44丝裂原激活蛋白激酶(MAPK)没有影响。Wortmannin和LY-294002的特异性进一步被证明这些化合物不能改变凝血酶诱导的钙瞬变、总PI水解或基础cAMP水平。瞬时表达具有结构性活性的PtdIns3-K(p110*)可激活pp70S6k，而显性负性PtdIns3-Kinase(ΔP85)则可阻断EGF和凝血酶刺激的pp70S6k的活性。总之，这些数据表明，PtdIns 3-激酶的激活是EGF和凝血酶在人ASM细胞中有丝分裂作用所必需的。对PtdIns3-Kinase作用的进一步研究可能会为哮喘和慢性支气管炎等以平滑肌细胞增生为特征的疾病的治疗提供新的治疗方法。
Hypertrophy and hyperplasia of airway smooth muscle (ASM) are important pathological features that contribute to airflow obstruction in chronic severe asthma. Despite considerable research effort, the cellular mechanisms that modulate ASM growth remain unknown. Recent evidence suggests that mitogen-induced activation of phosphoinositide (PI)-specific phospholipase C (PLC) and PI-dependent calcium mobilization are neither sufficient nor necessary to stimulate human ASM proliferation. In this study, we identify phosphatidylinositol (PtdIns) 3-kinase as a key regulator of human ASM proliferation. Pretreatment of human ASM with the PtdIns 3-kinase inhibitors wortmannin and LY-294002 significantly reduced thrombin- and epidermal growth factor (EGF)-induced DNA synthesis (IC50∼10 nM and ∼3 μM, respectively). In separate experiments, wortmannin and LY-294002 markedly inhibited PtdIns 3-kinase and 70-kDa S6 protein kinase (pp70S6k) activation induced by stimulation of human ASM cells with EGF and thrombin but had no effect on EGF- and thrombin-induced p42/p44 mitogen-activated protein kinase (MAPK) activation. The specificity of wortmannin and LY-294002 was further suggested by the demonstrated inability of these compounds to alter thrombin-induced calcium transients, total PI hydrolysis, or basal cAMP levels. Transient expression of constitutively active PtdIns 3-kinase (p110*) activated pp70S6k, whereas a dominant-negative PtdIns 3-kinase (Δp85) blocked EGF- and thrombin-stimulated pp70S6kactivity. Collectively, these data suggest that activation of PtdIns 3-kinase is required for the mitogenic effect of EGF and thrombin in human ASM cells. Further investigation of the role of PtdIns 3-kinase may offer new therapeutic approaches in the treatment of diseases characterized by smooth muscle cell hyperplasia such as asthma and chronic bronchitis.
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影响因子：
--
作者：
PANETTIERI, RA;MURRAY, RK;KOTLIKOFF, MI
通讯作者：
KOTLIKOFF, MI
DOI：
--
发表时间：
1985-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
G. Grynkiewicz;M. Poenie;Roger Y. TsienB
通讯作者：
G. Grynkiewicz;M. Poenie;Roger Y. TsienB
血管平滑肌细胞中磷脂酰肌醇 3 激酶活性的解离和有丝分裂抑制。
影响因子：
4.8
作者：
R. Weiss;Anthony Apostolidis
通讯作者：
Anthony Apostolidis
DOI：
10.1073/pnas.91.19.9185
发表时间：
1994-09-13
影响因子：
11.1
作者：
ROCHE, S;KOEGL, M;COURTNEIDGE, SA
通讯作者：
COURTNEIDGE, SA
影响因子：
4.1
作者：
Domin, J;Pages, F;Waterfield, MD
通讯作者：
Waterfield, MD