Yin X Y, Grove L, Datta N S, Katula K, Long M W, Prochownik E V
Section of Hematology/Oncology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Cancer Res. 2001 Sep 1;61(17):6487-93.
We have shown previously that mitotic spindle inhibitors allow the c-Myconcoprotein to uncouple mitosis from DNA synthesis, resulting in the acquisition of tetraploidy. This can also occur in the absence of spindle inhibition if c-Myc deregulation is combined with inactivation of the p53 tumor suppressor. Under these conditions, cyclin B1 protein is induced but retains its normal cell cycle regulation. We now show that the cyclin B1 promoter is directly but oppositely regulated by c-Myc and p53. Enforced expression of cyclin B1 also induces tetraploidy, either after mitotic spindle inhibition or in the absence of such inhibition if cyclin B1 is coexpressed with c-Myc. Cyclin B1 represents a new class of c-Myc target genes that is also regulated by p53. It is also the first identified downstream effector of c-Myc able to produce the chromosomal instability that characterizes virtually all tumor cells.
我们之前已经表明，有丝分裂纺锤体抑制剂可使c-Myc原癌蛋白将有丝分裂与DNA合成解偶联，从而导致四倍体的获得。如果c-Myc失调与p53肿瘤抑制因子失活相结合，在没有纺锤体抑制的情况下也会发生这种情况。在这些条件下，细胞周期蛋白B1蛋白被诱导产生，但仍保持其正常的细胞周期调控。我们现在表明，细胞周期蛋白B1启动子受到c-Myc和p53的直接但相反的调控。在有丝分裂纺锤体抑制后，或者如果细胞周期蛋白B1与c-Myc共表达，在没有这种抑制的情况下，细胞周期蛋白B1的强制表达也会诱导四倍体。细胞周期蛋白B1代表了一类新的c-Myc靶基因，其也受p53调控。它也是第一个被鉴定出的c-Myc下游效应物，能够产生几乎所有肿瘤细胞所特有的染色体不稳定性。
