Chajry N, Martin P M, Pages G, Cochet C, Afdel K, Berthois Y
Laboratoire de Cancérologie Expérimentale, Faculté de Medecine Nord, Marseille, France.
Biochem Biophys Res Commun. 1994 Sep 15;203(2):984-90. doi: 10.1006/bbrc.1994.2279.
EGF is involved in the regulation of cell proliferation in normal as well as in neoplastic tissues. The A431 cells that over-express EGFR, display in vitro ambivalent growth properties in response to EGF, since stimulation induced by low concentrations (10(-12) M-10(-10) M) is reversed with increasing concentrations (10(-9) M-10(-8) M). To assess differential mechanisms of signal transduction that determine growth stimulatory and inhibitory activity, we have studied the MAP kinase activation induced by mitotic and antimitotic concentrations of EGF. We demonstrate that the presence of a growth stimulatory concentration of EGF (10(-12) M) leads to a moderate but persistent activation of p42 MAP kinase during all the time of the EGF treatment. Conversely, an early peak of kinase activation that rapidly falls down below the basal level, is observed when a growth inhibitory concentration of EGF (10(-8) M) is used. Moreover, the addition of Na-orthovanadate in 10(-8) M EGF-treated cells leads to the rescue of the MAP kinase activity, suggesting that the loss of kinase activity induced by growth inhibitory EGF concentrations involves the dephosphorylation of the MAP kinase. In conclusion, our data demonstrate that the dual effect (stimulator/inhibitor) of EGF on the proliferation of A431 cells is associated to differential mechanisms of p42 MAP kinase regulation.
表皮生长因子（EGF）参与正常组织和肿瘤组织中细胞增殖的调节。过度表达表皮生长因子受体（EGFR）的A431细胞，在体外对EGF呈现出矛盾的生长特性，因为低浓度（10⁻¹²M - 10⁻¹⁰M）诱导的刺激会随着浓度增加（10⁻⁹M - 10⁻⁸M）而逆转。为了评估决定生长刺激和抑制活性的信号转导差异机制，我们研究了有丝分裂和抗有丝分裂浓度的EGF诱导的丝裂原活化蛋白激酶（MAP激酶）激活情况。我们证明，存在生长刺激浓度的EGF（10⁻¹²M）会在EGF处理的整个过程中导致p42 MAP激酶适度但持续的激活。相反，当使用生长抑制浓度的EGF（10⁻⁸M）时，会观察到激酶激活的早期峰值，该峰值会迅速降至基础水平以下。此外，在10⁻⁸M EGF处理的细胞中添加原钒酸钠会导致MAP激酶活性恢复，这表明生长抑制性EGF浓度诱导的激酶活性丧失涉及MAP激酶的去磷酸化。总之，我们的数据表明，EGF对A431细胞增殖的双重作用（刺激/抑制）与p42 MAP激酶调节的差异机制有关。
