Since little is known about the function of polypeptide growth factors as regulators of multiple cell cycles, we compared the ability of FGF1, PDGF-AB and serum to induce a second round of DNA synthesis in Swiss 3T3 cells previously exposed to either FGF1, PDGF-AB or serum during the first cell cycle using [14C]- and [3H]thymidine in a double labeling system to distinguish between the first and second cell cycles. Surprisingly, we observed that cells exposed to either FGF1 or PDGF-AB in the first cell cycle were unable to synthesize DNA in response to FGF1 or PDGF-AB in the second cell cycle; yet these cells responded well to serum as a second cycle mitogen. Interestingly, while cells exposed to either FGF1 or PDGF-AB in the second cycle displayed normal receptor-mediated signaling and expressed cyclin D and E, they, like senescent fibroblasts and endothelial cells, failed to express cyclin A, and the continuous exposure of cells to either FGF1 or PDGF-AB resulted in a decrease in the kinase activity of the cyclin E/cdk2 complex. In addition, an increased association of this complex was observed with p21 CIP in an FGF1-dependent manner as well as with p27 KIP in a PDGF-AB-dependent manner. Lastly, the downregulation of p21 expression using an antisense strategy was able to partially rescue the replicative response of Swiss 3T3 cells to FGF1 in the second cycle. These data suggest that (i) FGF1 and PDGF-AB may limit their mitogenic effect to a single cell cycle, (ii) entry into the second round of replication is serum dependent and (iii) the self-limiting nature of FGF1 and PDGF-AB correlates with the accumulation of the cdk inhibitors, p21 and p27, respectively.

中文翻译：

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单个多肽生长因子对静止细胞的刺激仅限于一个细胞周期。

由于对多肽生长因子作为多个细胞周期调控因子的功能了解甚少，我们比较了FGF1，PDGF-AB和血清在先前暴露于FGF1，PDGF-S的Swiss 3T3细胞中诱导第二轮DNA合成的能力。在第一个细胞周期中，使用AB或血清在双标记系统中使用[14C]-和[3H]胸苷来区分第一和第二个细胞周期。令人惊讶的是，我们观察到在第一个细胞周期中暴露于FGF1或PDGF-AB的细胞无法在第二个细胞周期中响应FGF1或PDGF-AB合成DNA。但是这些细胞对血清作为第二周期促分裂原的反应良好。有趣的是，虽然在第二个周期中暴露于FGF1或PDGF-AB的细胞显示出正常的受体介导信号并表达了细胞周期蛋白D和E，但它们 像衰老的成纤维细胞和内皮细胞一样，它们不能表达细胞周期蛋白A，并且细胞连续暴露于FGF1或PDGF-AB会导致细胞周期蛋白E / cdk2复合物的激酶活性降低。另外，观察到该复合物与FGF21依赖性的p21 CIP以及与PDGF-AB依赖性的p27 KIP的缔合增加。最后，在第二个周期中，使用反义策略下调p21表达能够部分挽救Swiss 3T3细胞对FGF1的复制反应。这些数据表明（i）FGF1和PDGF-AB可能将其促有丝分裂作用限制在单个细胞周期内；（ii）进入第二轮复制是血清依赖性的；并且（iii）FGF1和PDGF-AB的自限性AB与cdk抑制剂p21和p27的积累有关，