Lai K, Wang H, Lee W S, Jain M K, Lee M E, Haber E
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Massachusetts 02115. USA.
J Clin Invest. 1996 Oct 1;98(7):1560-7. doi: 10.1172/JCI118949.
Smooth muscle cell proliferation and migration is important in arteriosclerosis. In this process, cytokines and growth factors are upregulated and bind to their respective receptors, which in turn stimulate mitogen-activated protein (MAP) kinases. MAP kinases then relay signals to the nucleus that activate quiescent smooth muscle cells. Phosphatases downregulate MAP kinases. We investigated the role of a dual-specificity tyrosine phosphatase, MAP kinase phosphatase-1 (MKP-1), in smooth muscle cell proliferation. MKP-1 expression was high in arterial tissue by Northern analysis, and MKP-1 message was detected mainly in the arterial smooth muscle layer by in situ hybridization. After balloon injury of the rat carotid artery, expression of MKP-1 decreased greatly, whereas that of MAP kinases, especially p44 MAP kinase, increased. The time course of the reduction in MKP-1 message correlated with increased tyrosine phosphorylation and elevated p44 MAP kinase enzymatic activity. In rat arterial smooth muscle cells overexpressing MKP-1, growth was arrested in the G1 phase and entry into the S phase was blocked. A reduction in MKP-1 expression may contribute in part to proliferation of smooth muscle cells after vascular injury, possibly through a decrease in dephosphorylation of p44 MAP kinase.
平滑肌细胞的增殖和迁移在动脉粥样硬化过程中起着重要作用。在此过程中，细胞因子和生长因子上调并与其各自的受体结合，进而刺激丝裂原活化蛋白（MAP）激酶。MAP激酶随后将信号传递至细胞核，激活静止的平滑肌细胞。磷酸酶可下调MAP激酶。我们研究了双特异性酪氨酸磷酸酶——MAP激酶磷酸酶-1（MKP-1）在平滑肌细胞增殖中的作用。通过Northern印迹分析发现，MKP-1在动脉组织中的表达较高，并且通过原位杂交检测到MKP-1的信使核糖核酸主要存在于动脉平滑肌层。大鼠颈动脉球囊损伤后，MKP-1的表达大幅下降，而MAP激酶，尤其是p44 MAP激酶的表达增加。MKP-1信使核糖核酸减少的时间进程与酪氨酸磷酸化增加及p44 MAP激酶酶活性升高相关。在过表达MKP-1的大鼠动脉平滑肌细胞中，细胞生长停滞于G1期，进入S期受阻。MKP-1表达的降低可能部分促成了血管损伤后平滑肌细胞的增殖，这可能是通过减少p44 MAP激酶的去磷酸化来实现的。
