Zhang D, Jacobberger J W
Cancer Research Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Cell Prolif. 1996 Jun;29(6):289-307. doi: 10.1111/j.1365-2184.1996.tb01581.x.
We have demonstrated previously that SV40 T antigen and serum regulate the length of G1 in exponentially growing NIH-3T3 cells in part by inhibiting density dependent negative cell cycle regulation. In these studies it was suggested that T antigen positively regulated G1 in a density independent manner as well. In this report we show that, 24 h after treatment, TGF-beta 1 perturbs the cell cycle of exponentially growing fibroblasts in a manner similar to T antigen. However, prior to 24 h, TGF-beta 1 produced a negative response, elongating the G1 phase of the cell cycle that was followed by a positive response, both of which were density independent. This biphasic response was measured between 0 and 12 h post-treatment and was relative to responses from serum. This switch from an early inhibitory effect to a late stimulatory effect was associated with changes in Rb phosphorylation, the timing and magnitude of which indicated that Rb may be directly regulating TG1 rather than reporting changes in the population. This is further substantiated by abrogation of the inhibitory effect by expression of wild-type SV40 T antigen and retention of the effect in cells that express an Rb-binding mutant of T antigen (K1). The biphasic regulatory effects of TGF-beta 1 were also displayed in WI-38 and IMR-90 human fibroblasts. This suggests that this biphasic effect is a property of fibroblasts.
我们之前已经证明，SV40 T抗原和血清部分通过抑制密度依赖性负性细胞周期调控来调节指数生长的NIH-3T3细胞中G1期的长度。在这些研究中还表明，T抗原也以密度非依赖性方式正向调节G1期。在本报告中，我们显示，处理24小时后，TGF-β1以类似于T抗原的方式扰乱指数生长的成纤维细胞的细胞周期。然而，在24小时之前，TGF-β1产生了负反应，延长了细胞周期的G1期，随后是正反应，这两种反应均与密度无关。这种双相反应在处理后0至12小时之间测得，并且相对于血清的反应。从早期抑制作用到晚期刺激作用的这种转变与Rb磷酸化的变化有关，其时间和幅度表明Rb可能直接调节TG1而不是报告群体中的变化。野生型SV40 T抗原的表达消除了抑制作用，而在表达T抗原的Rb结合突变体（K）的细胞中保留了该作用，这进一步证实了这一点。TGF-β1的双相调节作用也在WI-38和IMR-90人成纤维细胞中表现出来。这表明这种双相作用是成纤维细胞的一种特性。
