Antiprogestin inhibition of cell cycle progression in T-47D breast cancer cells is accompanied by induction of the cyclin-dependent kinase inhibitor p21
Antiprogestin inhibition of cell cycle progression in T-47D breast cancer cells is accompanied by induction of the cyclin-dependent kinase inhibitor p21
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DOI：
10.1210/me.11.1.54
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发表时间：
1997-01-01
影响因子：
--
通讯作者：
Sutherland, RL
中科院分区：
文献类型：
--
作者：
Musgrove, EA;Lee, CSL;Sutherland, RL
孕激素拮抗剂通过G（1）期特异性作用抑制孕激素受体阳性细胞（包括乳腺癌细胞）的增殖，但涉及的分子靶点尚未确定。用抗孕激素RU 486或ORG 31710处理T-47 D乳腺癌细胞9小时后，体内G（1）细胞周期蛋白依赖性激酶（CDKs）的底物pRB的磷酸化明显减少，同时S期分数也发生变化。尽管细胞周期蛋白D1、Cdk 4和Cdk 6的丰度没有降低，但细胞周期蛋白D1相关激酶活性在9-18 h时降低了约50%。类似地，在细胞周期蛋白E和Cdk 2丰度没有显著变化的情况下，细胞周期蛋白E相关激酶活性在12-24小时降低了60%。CDK抑制剂p21的mRNA和蛋白质丰度增加，并在细胞周期蛋白D1和细胞周期蛋白E复合物的时候，他们的激酶活性降低，目前在增加的水平。在另一个抗孕激素敏感的细胞系BT 474中观察到p21蛋白丰度增加，但在两个抗孕激素不敏感的乳腺癌细胞系中没有观察到。这些数据表明，增加p21丰度和CDK活性的抑制作为一种机制，为antiresistin诱导生长停滞。antibacteriostin对增殖的影响显着减少后，异位表达的细胞周期蛋白D1，表明抑制细胞周期蛋白D1的功能是antibacteriostin抑制增殖的一个关键因素。然而，这些数据也暗示了细胞周期蛋白E的功能调节在细胞周期进程的抗resistin调节。
Progestin antagonists inhibit the proliferation of progesterone receptor-positive cells, including breast cancer cells, by G(1) phase-specific actions, but the molecular targets involved are not defined. Reduced phosphorylation of pRB, a substrate for G(1) cyclin-dependent kinases (CDKs) in vivo, was apparent after 9 h treatment of T-47D breast cancer cells with the antiprogestins RU 486 or ORG 31710, accompanying changes in S phase fraction. Although the abundance of cyclin D1, Cdk4, and Cdk6 did not decrease, cyclin D1-associated kinase activity was reduced by similar to 50% at 9-18 h. Similarly, cyclin E-associated kinase activity decreased by similar to 60% at 12-24 h in the absence of significant changes in the abundance of cyclin E and Cdk2. The CDK inhibitor p21 increased in mRNA and protein abundance and was present at increased levels in cyclin D1 and cyclin E complexes at times when their kinase activity was decreased. Increased p21 protein abundance was observed in another antiprogestin-sensitive cell line, BT 474, but not in two breast cancer cell lines insensitive to antiprogestins. These data suggest increased p21 abundance and concurrent inhibition of CDK activity as a mechanism for antiprogestin induction of growth arrest. Antiprogestin effects on proliferation were markedly reduced after ectopic expression of cyclin D1, indicating that inhibition of cyclin D1 function is a critical element in antiprogestin inhibition of proliferation. However, these data also implicate regulation of cyclin E function in antiprogestin regulation of cell cycle progression.