Weiss R H, Yabes A P, Sinaee R
Department of Internal Medicine, Northern California System of Clinics, Pleasant Hill, USA.
Kidney Int. 1995 Sep;48(3):738-44. doi: 10.1038/ki.1995.345.
Transforming growth factor (TGF)-beta mediates matrix production in both mesangial and vascular smooth muscle cells. Both TGF-beta and phorbol-12-myristate-13-acetate (PMA) exert both positive and negative effects on mitogenesis in these as well as other cell types. Phorbol esters act through stimulation of protein kinase C (PKC) and are among the most potent tumor promoters known. The present study was conducted to determine if the growth inhibitory effect of TGF-beta parallels that of the phorbol esters and whether this effect of TGF-beta is dependent on activation of PKC. We show that, in vascular smooth muscle cells stimulated to divide by the addition of the serum component basic fibroblast growth factor (bFGF), TGF-beta1 inhibits mitogenesis in a dose-dependent manner, by a maximum of 79% when applied at a concentration of 1 ng/ml. Furthermore, the inhibitory effect on mitogenesis of either TGF-beta1 or PMA, when added four hours after bFGF, are 71% and 84% respectively. Both TGF-beta1 and PMA cause translocation of celllular PKC with similar time courses, while neither PKC-alpha nor PKC-betaII are increased in quantity in response to TGF-beta1. In addition, down-regulation of PKC by 24 hours incubation with PMA abolishes TGF-beta's inhibitory effect in bFGF-stimulated cells. We conclude that (i) the signaling pathway utilized by TGF-beta resulting in inhibition of mitogenesis parallels that of PMA, and (ii) the inhibitory effect of TGF-beta1 on bFGF-induced mitogenesis is partially due to activation of PKC. These data suggest that TGF-beta may be an endogenous activator of the growth-inhibitory pathway of PKC, and, since cellular differentiated functions generally occur when the cells are proliferation-inhibited, PKC may be a modulator of extracellular matrix deposition.
转化生长因子（TGF）-β介导系膜细胞和血管平滑肌细胞中的基质生成。TGF-β和佛波醇-12-肉豆蔻酸酯-13-乙酸酯（PMA）对这些细胞以及其他细胞类型的有丝分裂都有正负两方面的影响。佛波醇酯通过刺激蛋白激酶C（PKC）起作用，是已知的最有效的肿瘤促进剂之一。本研究旨在确定TGF-β的生长抑制作用是否与佛波醇酯相似，以及TGF-β的这种作用是否依赖于PKC的激活。我们发现，在通过添加血清成分碱性成纤维细胞生长因子（bFGF）刺激分裂的血管平滑肌细胞中，TGF-β1以剂量依赖的方式抑制有丝分裂，当以1 ng/ml的浓度应用时，最大抑制率可达79%。此外，在bFGF添加4小时后添加TGF-β1或PMA，对有丝分裂的抑制作用分别为71%和84%。TGF-β1和PMA都能使细胞PKC发生转位，且时间进程相似，而TGF-β1不会使PKC-α或PKC-βII的数量增加。此外，用PMA孵育24小时使PKC下调，可消除TGF-β在bFGF刺激细胞中的抑制作用。我们得出结论：（i）TGF-β导致有丝分裂抑制的信号通路与PMA相似；（ii）TGF-β1对bFGF诱导的有丝分裂的抑制作用部分归因于PKC的激活。这些数据表明，TGF-β可能是PKC生长抑制途径的内源性激活剂，而且，由于细胞分化功能通常在细胞增殖受抑制时出现，PKC可能是细胞外基质沉积的调节剂。
