Induction of cyclin D1 transcription and CDK2 activity by Notchic:: Implication for cell cycle disruption in transformation by Notchic
Induction of cyclin D1 transcription and CDK2 activity by Notchic:: Implication for cell cycle disruption in transformation by Notchic
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DOI：
10.1128/mcb.21.17.5925-5934.2001
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发表时间：
2001-09-01
影响因子：
5.3
通讯作者：
Capobianco, AJ
中科院分区：
文献类型：
--
作者：
Ronchini, C;Capobianco, AJ
Notch基因编码一个跨膜蛋白家族，参与许多细胞过程，如分化、增殖和凋亡。虽然已经确定所有四个Notch基因都可以作为致癌基因，但Notch蛋白转化细胞的机制仍然未知。以前，我们已经表明，RKE细胞的转化可以有条件地诱导Notch（IC）-雌激素受体（ER）嵌合体的激素激活。使用这种诱导系统，我们表明，Notch（IC）激活细胞周期蛋白D1基因的转录与快速动力学。细胞周期蛋白D1的转录激活不依赖于血清衍生的生长因子和二级转录激活因子的从头合成。此外，Notch（ic）-ER蛋白的激素活化在不存在血清的情况下诱导CDK 2活性。通过Notch（ic）上调细胞周期蛋白D1和激活CDK 2导致S期进入的促进。这些数据证明了Notch（ic）蛋白可以直接调节参与细胞周期控制的因子并影响细胞增殖的第一个证据。此外，nontransforming Notch（ic）蛋白不诱导细胞周期蛋白D1的表达，表明通过细胞周期蛋白D1的组成性表达的转化机制涉及细胞周期失调。最后，我们已经确定了CSL [代表CBF 1，Su（H），和Lag-1]结合位点内的人类和大鼠细胞周期蛋白D1的启动子，表明Notchic蛋白激活细胞周期蛋白D1的转录通过CSL依赖的途径。
Notch genes encode a family of transmembrane proteins that are involved in many cellular processes such as differentiation, proliferation, and apoptosis. Although it is well established that all four Notch genes can act as oncogenes, the mechanism by which Notch proteins transform cells remains unknown. Previously, we have shown that transformation of RKE cells can be conditionally induced by hormone activation of Notch(ic)-estrogen receptor (ER) chimeras. Using this inducible system, we show that Notch(ic) activates transcription of the cyclin D1 gene with rapid kinetics. Transcriptional activation of cyclin D1 is independent from serum-derived growth factors and de novo synthesis of secondary transcriptional activators. Moreover, hormone activation of Notch(ic)-ER proteins induces CDK2 activity in the absence of serum. Upregulation of cyclin D1 and activation of CDK2 by Notch(ic) result in the promotion of S-phase entry. These data demonstrate the first evidence that Notch(ic) proteins can directly regulate factors involved in cell cycle control and affect cellular proliferation. Furthermore, nontransforming Notch(ic) proteins do not induce cyclin D1 expression, indicating that the mechanism of transformation involves cell cycle deregulation through constitutive expression of cyclin D1. Finally, we have identified a CSL [stands for CBF1, Su(H), and Lag-1] binding site within the human and rat cyclin D1 promoters, suggesting that Notchic proteins activate cyclin D1 transcription through a CSL-dependent pathway.