Rieber M, Rieber M S
Instituto Venezolano de Investigaciones Científicas, Tumor cell Biology Laboratory, Caracas, Venezuela.
Cell Growth Differ. 1994 Dec;5(12):1339-46.
L-Tyrosine promotes a dramatic increase in melanogenesis and an apparent replicative senescence in B16 melanoma (M. Strasberg-Rieber and M. Rieber, Cancer Res., 53:2469-2471, 1993). Since cyclins are implicated in controlling cell proliferation and differentiation, we have now investigated their relationship to melanocytic growth arrest and pigmentation. In B16 melanoma cells enriched in G1 by serum starvation or synchronized in late G1/early S phase by exposure to hydroxyurea, L-tyrosine overrides mitogenic signals and induces terminal differentiation without cytotoxicity. This correlates with a decrease in cyclin A and cyclin E-dependent kinase 2 activity and with an altered interaction of cyclin A with the transcription factor E2F. This activity involves a lower level of the catalytic cdK2 kinase protein without a concomitant decrease in cyclin A or cyclin E. Upon addition of serum or removal of hydroxyurea, cells resume cell cycle progression and the ability to form tumors in vivo, but these properties are irreversibly inhibited in tyrosine-treated cells. Our data suggest that targeted inactivation of cdK2 with specific inducers of differentiation favors reacquisition of tumor growth control.
L-酪氨酸可显著促进B16黑色素瘤细胞的黑色素生成，并导致明显的复制性衰老（M. Strasberg-Rieber和M. Rieber，《癌症研究》，53:2469 - 2471，1993）。由于细胞周期蛋白与细胞增殖和分化的调控有关，我们现在研究了它们与黑素细胞生长停滞和色素沉着的关系。在通过血清饥饿使G1期富集或通过暴露于羟基脲使其同步于G1晚期/ S期早期的B16黑色素瘤细胞中，L-酪氨酸可超越有丝分裂原信号并诱导终末分化而无细胞毒性。这与细胞周期蛋白A和细胞周期蛋白E依赖性激酶2活性的降低以及细胞周期蛋白A与转录因子E2F相互作用的改变相关。这种活性涉及催化性cdK2激酶蛋白水平的降低，而细胞周期蛋白A或细胞周期蛋白E没有相应减少。加入血清或去除羟基脲后，细胞恢复细胞周期进程并恢复在体内形成肿瘤的能力，但这些特性在酪氨酸处理的细胞中被不可逆地抑制。我们的数据表明，用特定的分化诱导剂靶向灭活cdK2有利于重新获得肿瘤生长控制。
