期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 21, 期 17, 页码 5925-5934出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.21.17.5925-5934.2001
关键词
-
资金
- NCI NIH HHS [R01 CA083736, R01 CA 83736] Funding Source: Medline
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据