β-hexosaminidase-induced activation of p44/42 mitogen-activated protein kinase is dependent on p21Ras and protein kinase C and mediates bovine airway smooth-muscle proliferation
β-hexosaminidase-induced activation of p44/42 mitogen-activated protein kinase is dependent on p21Ras and protein kinase C and mediates bovine airway smooth-muscle proliferation
复制标题
DOI：
10.1165/ajrcmb.21.1.3542
复制
发表时间：
1999-07-01
影响因子：
6.4
通讯作者：
Malik, KU
中科院分区：
文献类型：
--
作者：
Lew, DB;Dempsey, BK;Malik, KU
据报道，p44/42（MAPK）的晚期和持续激活是细胞有丝分裂发生中的关键因素。因此，我们假设p44/42（MAPK）参与了富含甘露糖基的糖蛋白诱导的牛气道平滑肌细胞（ASMC）的有丝分裂。用β-氨基己糖苷酶A（Hex A，50 nM）（一种内源性富含甘露糖基的糖蛋白）处理粘附的ASMC，导致p44/42（MAPK）的迟发性（30 min）激活，持续4 h。硫代磷酸衍生的反义寡核苷酸抑制Hex A诱导的p44/42 MAPK活化（1-5 μ M）;促分裂原活化蛋白激酶激酶（MEK 1）抑制剂PD 98059（5 μ M）; p42（MAPK）抑制剂Tyrphostin AG-126（0.2 μ M）;法尼基转移酶抑制剂SCH-56582（10 μ M）和FPT III（10 μ M），其抑制p21 Ras活化;以及Calphostin C（0.2 μ M），一种蛋白激酶C抑制剂。这些药物也抑制Hex A诱导的牛ASMC细胞增殖。这些数据表明，Hex A激活p44/42（MAPK）在p21 Ras和PKC依赖的方式，这种激活介导的Hex A诱导的有丝分裂在牛ASMC。
Late-phase and sustained activation of p44/42(MAPK) has been reported to be a critical factor in cell mitogenesis. We therefore hypothesized that p44/42(MAPK) is involved in mannosyl-rich glycoprotein-induced mitogenesis in bovine airway smooth-muscle cells (ASMC). Treatment of adherent ASMC with beta-hexosaminidase A (Hex A, 50 nM), an endogenous mannosyl-rich glycoprotein, resulted in a late-onset (30-min) activation of p44/42(MAPK) that lasted for 4 h. Activation of p44/42MAPK induced by Hex A was inhibited by an 18-mer phosphorothioate-derivatized antisense oligonucleotide (1-5 mu M) directed to human p44(MAPK); the mitogen-activated protein kinase kinase (MEK1) inhibitor PD98059 (5 mu M); the p42(MAPK) inhibitor Tyrphostin AG-126 (0.2 mu M); the farnesyl transferase inhibitors SCH-56582 (10 mu M) and FPT III (10 mu M), which inhibit p21Ras activation; and Calphostin C (0.2 mu M), an inhibitor of protein kinase C. These agents also inhibited Hex A-induced cell proliferation in bovine ASMC, These data suggest that Hex A activates p44/42(MAPK) in a p21Ras- and PKC-dependent manner and that this activation mediates Hex A-induced mitogenesis in bovine ASMC.