Tabruyn Sébastien P, Nguyen Ngoc-Quynh-Nhu, Cornet Anne M, Martial Joseph A, Struman Ingrid
Laboratoire de Biologie Moléculaire et de Génie Génétique, Université de Liège, Allée du 6 Aout B6A, B-4000 Liège, Belgium.
Mol Endocrinol. 2005 Jul;19(7):1932-42. doi: 10.1210/me.2004-0515. Epub 2005 Mar 3.
The 16-kDa N-terminal fragment of human prolactin (16K hPRL) is a potent antiangiogenic factor that has been shown to prevent tumor growth in a xenograph mouse model. In this paper we first demonstrate that 16K hPRL inhibits serum-induced DNA synthesis in adult bovine aortic endothelial cells. This inhibition is associated with cell cycle arrest at both the G(0)-G(1) and the G(2)-M phase. Western blot analysis revealed that 16K hPRL strongly decreases levels of cyclin D1 and cyclin B1, but not cyclin E. The effect on cyclin D1 is at least partially transcriptional, because treatment with 16K hPRL both reduces the cyclin D1 mRNA level and down-regulates cyclin D1 promoter activity. This regulation may be due to inhibition of the MAPK pathway, but it is independent of the glycogen synthase kinase-3beta pathway. Lastly, 16K hPRL induces the expression of negative cell cycle regulators, the cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1). In summary, 16K hPRL inhibits serum-induced proliferation of endothelial cells through combined effects on positive and negative regulators of cell cycle progression.
人催乳素16 kDa N端片段（16K hPRL）是一种有效的抗血管生成因子，已证实在异种移植小鼠模型中可抑制肿瘤生长。在本文中，我们首先证明16K hPRL可抑制成年牛主动脉内皮细胞中血清诱导的DNA合成。这种抑制作用与细胞周期在G(0)-G(1)期和G(2)-M期均停滞有关。蛋白质印迹分析显示，16K hPRL可显著降低细胞周期蛋白D1和细胞周期蛋白B1的水平，但不影响细胞周期蛋白E的水平。对细胞周期蛋白D1的影响至少部分是转录水平的，因为用16K hPRL处理可降低细胞周期蛋白D1的mRNA水平并下调细胞周期蛋白D1启动子活性。这种调节可能是由于丝裂原活化蛋白激酶（MAPK）途径受到抑制，但与糖原合酶激酶-3β途径无关。最后，16K hPRL可诱导细胞周期负调控因子——细胞周期蛋白依赖性激酶抑制剂p21(cip1)和p27(kip1)的表达。总之，16K hPRL通过对细胞周期进程的正调控因子和负调控因子的联合作用，抑制血清诱导的内皮细胞增殖。
