CYCLIN D1 INDUCTION IN BREAST-CANCER CELLS SHORTENS G(1) AND IS SUFFICIENT FOR CELLS ARRESTED IN G(1) TO COMPLETE THE CELL-CYCLE
CYCLIN D1 INDUCTION IN BREAST-CANCER CELLS SHORTENS G(1) AND IS SUFFICIENT FOR CELLS ARRESTED IN G(1) TO COMPLETE THE CELL-CYCLE
复制标题
DOI：
10.1073/pnas.91.17.8022
复制
发表时间：
1994-08-16
影响因子：
11.1
通讯作者：
SUTHERLAND, RL
中科院分区：
文献类型：
--
作者：
MUSGROVE, EA;LEE, CSL;SUTHERLAND, RL
细胞周期蛋白（细胞周期特异性激酶的调节亚基）的顺序转录激活被认为调节细胞周期的进程。因此，细胞周期蛋白是潜在的致癌基因，细胞周期蛋白D1在其基因组位点11 q13的过表达和/或扩增是几种人类癌症的共同特征。细胞周期蛋白D1的诱导是几种细胞类型对促有丝分裂刺激的早期反应，但该基因在上皮来源的人类细胞中表达改变的后果仍不确定。我们通过在锌响应金属硫蛋白启动子的控制下产生表达人细胞周期蛋白D1的T-47 D细胞，评估了细胞周期蛋白D1表达改变对人乳腺癌细胞的影响。在周期细胞中，锌处理后细胞周期蛋白D1的诱导导致通过G（1）期的细胞数量增加和从G（1）期向S期转变的速率增加，表明细胞周期蛋白D1是通过G（1）期的速度限制。在生长因子剥夺后停滞在早期G（1）期的细胞中，锌对细胞周期蛋白D1的诱导足以完成细胞周期，这是一个在对照细胞中需要生长因子刺激的过程。这些数据表明细胞周期蛋白D1在人乳腺癌细胞周期控制中的关键作用，并表明细胞周期蛋白D1的表达失调可能会减少对正常生理生长刺激的依赖，从而为肿瘤细胞提供生长优势和对内分泌治疗的潜在耐药机制。
The sequential transcriptional activation of cyclins, the regulatory subunits of cell-cycle-specific kinases, is thought to regulate progress through the cell cycle. Cyclins are therefore potential oncogenes, and cyclin D1 overexpression and/or amplification at its genomic locus, 11q13, are common features of several human cancers. Induction of cyclin D1 is an early response to mitogenic stimulation in several cell types, but the consequences of altered expression of this gene in human cells of epithelial origin remain undefined. We assessed the effects of alterations of cyclin D1 expression in human breast cancer cells by generating T-47D cells expressing human cyclin D1 under the control of a zinc-responsive metallothionein promoter. In cycling cells induction of cyclin D1 after zinc treatment resulted in an increase in the number of cells progressing through G(1) and in the rate of transition from G(1) to S phase, indicating that cyclin D1 is rate-limiting for progress through G(1) phase, In cells arrested in early G(1) phase after growth factor deprivation, zinc induction of cyclin D1 was sufficient for completion of the cell cycle, a process requiring growth factor stimulation in control cells. These data demonstrate a critical role for cyclin D1 in human breast cancer cell-cycle control and suggest that deregulated expression of cyclin D1 is likely to reduce dependence on normal physiological growth stimuli, thereby providing a growth advantage to tumor cells and a potential mechanism of resistance to endocrine therapy.