Dynein light chain 1 contributes to cell cycle progression by increasing cyclin-dependent kinase 2 activity in estrogen-stimulated cells
Dynein light chain 1 contributes to cell cycle progression by increasing cyclin-dependent kinase 2 activity in estrogen-stimulated cells
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DOI：
10.1158/0008-5472.can-05-3480
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发表时间：
2006-06-01
期刊：
影响因子：
11.2
通讯作者：
Kumar, Rakesh
中科院分区：
文献类型：
--
作者：
den Hollander, Petra;Kumar, Rakesh
激素反应性癌症的进展以细胞周期和细胞骨架信号传导失调为特征。此外，乳腺癌和子宫内膜癌的发展受到雌激素刺激作用的影响。最近发现动力蛋白轻链 1 (DLC1)（细胞骨架信号传导的一个组成部分）的上调可促进肿瘤发生。我们研究的目的是确定 DLC1 上调在细胞周期进展中所起的作用。为了实现这一目标，我们使用过表达 DLC1 的人乳腺导管癌 ZR-75 细胞作为模型系统。我们发现，DLC1 上调的 ZR-75 细胞对雌激素依赖性生长刺激高度敏感，并且 DLC1 对 G(1)-S 转变具有加速作用，并刺激细胞周期蛋白依赖性激酶 2 (Cdk2) 活性。为了更好地了解 DLC1 对 G(1)-S 转变的促进作用，我们试图鉴定在细胞周期调节中发挥作用的新 DLC1 相互作用蛋白。使用改良的蛋白质组学策略，我们鉴定了两种这样的 DLC1 相互作用蛋白：Cdk2 和 Cip 相互作用锌指蛋白 I (Ciz1)。 DLC1 经验证可在体内与 Cdk2 和 Ciz1 相互作用。我们还发现，DLC1 和 Ciz1 的下调可降低乳腺癌 ZR-75 和 MCF-7 以及子宫内膜石川癌细胞的 Cdk2 活性和细胞周期进程。此外，我们发现 DLC1 的过度表达伴随着核 p21（WAF1）的减少。这些发现表明，DLC1、Cdk2 和 Ciz1 之间的相互作用可能通过影响核 p21 (WAF1) 的水平，在癌细胞的细胞周期进展中发挥调节作用。
Progression of hormone-responsive cancers is characterized by deregulation of the cell cycle and cytoskeleton signaling. In addition, development of breast and endometrial cancer is influenced by the stimulatory action of estrogen. Upregulation of dynein light chain 1 (DLC1), a component of cytoskeleton signaling, was recently found to promote tumorigenesis. The purpose of our study was to determine the role that DLC1 up-regulation plays in cell cycle progression. To achieve this goal, we used human breast ductal carcinoma ZR-75 cells overexpressing DLC1 as a model system. We found that ZR-75 cells with up-regulated DLC1 were hypersensitive to estrogen-dependent growth stimulation and that DLC1 had an accelerating effect on the G(1)-S transition and stimulated cyclin-dependent kinase 2 (Cdk2) activity. To better understand the promotion of the G(1)-S transition by DLC1, we sought to identify new DLC1-interacting proteins with roles in cell cycle regulation. Using a modified proteomic strategy, we identified two such DLC1-interacting proteins: Cdk2 and Cip-interacting zinc finger protein I (Ciz1). DLC1 was verified to interact with Cdk2 and Ciz1 in vivo. We also showed that down-regulation of DLC1 and Ciz1 reduced both Cdk2 activity and cell cycle progression of breast cancer ZR-75 and MCF-7 and endometrial Ishikawa cancer cells. Further, we showed that overexpression of DLC1 is accompanied by a reduction of nuclear p21(WAF1). These findings suggest that interactions among DLC1, Cdk2, and Ciz1 play a regulatory role in cell cycle progression of cancer cells presumably by influencing the levels of nuclear p21(WAF1).