Institute of Genetics and Biophysics Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche (CNR), Via P. Castellino 111, 80131 Naples, Italy.
Mol Cell Biol. 2010 Apr;30(7):1838-51. doi: 10.1128/MCB.01442-09. Epub 2010 Feb 1.
It has been proposed that c-Myc proapoptotic activity accounts for most of its restraint of tumor formation. We established a telomerase-immortalized human epithelial cell line expressing an activatable c-Myc protein. We found that c-Myc activation induces, in addition to increased sensitivity to apoptosis, reductions in cell motility and invasiveness. Transcriptome analysis revealed that urokinase (uPA) and uPA receptor (uPAR) were strongly downregulated by c-Myc. Evidence is provided that the repression of uPA and uPAR may account for most of the antimigratory and proapoptotic activities of c-Myc. c-Myc is known to cooperate with Ras in cellular transformation. We therefore investigated if this cooperation could converge in the control of uPA/uPAR expression. We found that Ras is able to block the effects of c-Myc activation on apoptosis and cellular motility but not on cell invasiveness. Accordingly, the activation of c-Myc in the context of Ras expression had only minor influence on uPAR expression but still had a profound repressive effect on uPA expression. Thus, the differential regulation of uPA and uPAR by c-Myc and Ras correlates with the effects of these two oncoproteins on cell motility, invasiveness, and survival. In conclusion, we have discovered a novel link between c-Myc and uPA/uPAR. We propose that reductions of cell motility and invasiveness could contribute to the inhibition of tumorigenesis by c-Myc and that the regulation of uPA and uPAR expression may be a component of the ability of c-Myc to reduce motility and invasiveness.
有人提出，c-Myc 的促凋亡活性解释了其对肿瘤形成的大部分抑制作用。我们建立了一个端粒酶永生化的人上皮细胞系，表达一种可激活的 c-Myc 蛋白。我们发现，c-Myc 的激活除了增加细胞对凋亡的敏感性外，还降低了细胞的迁移和侵袭能力。转录组分析显示，尿激酶 (uPA) 和 uPA 受体 (uPAR) 被 c-Myc 强烈下调。有证据表明，uPA 和 uPAR 的抑制可能解释了 c-Myc 的大部分抗迁移和促凋亡活性。众所周知，c-Myc 与 Ras 协同作用于细胞转化。因此，我们研究了这种协同作用是否可以集中在 uPA/uPAR 表达的控制上。我们发现 Ras 能够阻断 c-Myc 激活对细胞凋亡和细胞迁移的影响，但不能阻断对细胞侵袭的影响。因此，在 Ras 表达的背景下激活 c-Myc 对 uPAR 表达只有轻微的影响，但对 uPA 表达仍有显著的抑制作用。因此，c-Myc 和 Ras 对 uPA 和 uPAR 的不同调节与这两种癌蛋白对细胞迁移、侵袭和存活的影响相关。总之，我们发现了 c-Myc 和 uPA/uPAR 之间的一个新联系。我们提出，细胞迁移和侵袭的减少可能有助于 c-Myc 抑制肿瘤发生，而 uPA 和 uPAR 表达的调节可能是 c-Myc 降低迁移和侵袭能力的一个组成部分。
