Said T K, Luo L, Medina D
Baylor College of Medicine, Department of Cell Biology, Houston, TX 77030, USA.
Carcinogenesis. 1995 Oct;16(10):2507-13. doi: 10.1093/carcin/16.10.2507.
Deregulated expression of G1 cyclins D1 and D2 is a feature of some neoplasias. This study examined the altered expression of D1 and D2 cyclins, both the total pool and as associated with cdk4 and cdk2, at different stages of mouse mammary tumorigenesis. Three different mammary hyperplastic outgrowth lines, TM2, TM10 and TM12, and their respective tumors were examined. Increasing levels of the cyclin D1 protein pool, D1 binding to cdk4 and cdk2 and cdk4 kinase activity were closely correlated with tumorigenesis. In constrast, cyclin D2 binding to cdk4 was predominant in hyperplasias and much less in tumors, where cyclin D1 became predominant. However, the cyclin D2 pool showed increases of 15-65 times in hyperplasias compared with normal gland and further increases of 11-15 times in two of three different tumors. The message level for cyclin D1 increased only 2-3 times in tumors compared with normal gland. Cyclin D2 mRNA was highest in normal tissue and decreased only marginally in tumors. These results suggest that cyclin D2 functions uniquely from cyclin D1 in the early stages of mouse mammary tumor development. Cyclin D2 bound to cdk4 may act to guarantee a low level of kinase activity in hyperplasias and may be an attempt to direct the mammary epithelial cells through differentiation rather than proliferation. This interaction may be one of the negative regulatory mechanisms in the early stages in mouse mammary tumor development, until cyclin D1 totally replaces cyclin D2 binding to cdk4, which would activate the high levels of cdk4 kinase activity observed in neoplasias.
G1 细胞周期蛋白 D1 和 D2 的表达失调是某些肿瘤形成的一个特征。本研究检测了在小鼠乳腺肿瘤发生的不同阶段，细胞周期蛋白 D1 和 D2 的表达变化，包括总量以及与细胞周期蛋白依赖性激酶 4（cdk4）和细胞周期蛋白依赖性激酶 2（cdk2）相关的表达。研究了三种不同的乳腺增生性生长系 TM2、TM10 和 TM12 及其各自的肿瘤。细胞周期蛋白 D1 蛋白总量、D1 与 cdk4 和 cdk2 的结合以及 cdk4 激酶活性的增加与肿瘤发生密切相关。相比之下，细胞周期蛋白 D2 与 cdk4 的结合在增生组织中占主导，而在肿瘤中则少得多，在肿瘤中细胞周期蛋白 D1 占主导。然而，与正常腺体相比，细胞周期蛋白 D2 的总量在增生组织中增加了 15 - 65 倍，在三种不同肿瘤中的两种中进一步增加了 11 - 15 倍。与正常腺体相比，肿瘤中细胞周期蛋白 D1 的信使核糖核酸（mRNA）水平仅增加了 2 - 3 倍。细胞周期蛋白 D2 的 mRNA 在正常组织中最高，在肿瘤中仅略有下降。这些结果表明，在小鼠乳腺肿瘤发展的早期阶段，细胞周期蛋白 D2 的功能与细胞周期蛋白 D1 不同。与 cdk4 结合的细胞周期蛋白 D2 可能在增生组织中保证低水平的激酶活性，并可能是引导乳腺上皮细胞分化而非增殖的一种尝试。这种相互作用可能是小鼠乳腺肿瘤发展早期的负调控机制之一，直到细胞周期蛋白 D1 完全取代与 cdk4 结合的细胞周期蛋白 D2，这将激活在肿瘤中观察到的高水平 cdk4 激酶活性。
