| Autor: |
Lee, Richard J., Albanese, Chris, Fu, Maofu, D'Amico, Mark, Lin, Bing, Watanabe, Genichi, Haines, George K., Siegel, Peter M., Hung, Mien-Chie, Yarden, Yosef, Horowitz, Jonathan M., Muller, William J., Pestell, Richard G. |
| Zdroj: |
Molecular and Cellular Biology; January 2000, Vol. 20 Issue: 2 p672-683, 12p |
| Abstrakt: |
The neu(c-erbB-2) proto-oncogene encodes a tyrosine kinase receptor that is overexpressed in 20 to 30% of human breast tumors. Herein, cyclin D1 protein levels were increased in mammary tumors induced by overexpression of wild-type Neu or activating mutants of Neu in transgenic mice and in MCF7 cells overexpressing transforming Neu. Analyses of 12 Neu mutants in MCF7 cells indicated important roles for specific C-terminal autophosphorylation sites and the extracellular domain in cyclin D1 promoter activation. Induction of cyclin D1 by NeuT involved Ras, Rac, Rho, extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38, but not phosphatidylinositol 3-kinase. NeuT induction of the cyclin D1 promoter required the E2F and Sp1 DNA binding sites and was inhibited by dominant negative E2F-1 or DP-1. Neu-induced transformation was inhibited by a cyclin D1 antisense or dominant negative E2F-1 construct in Rat-1 cells. Growth of NeuT-transformed mammary adenocarcinoma cells in nude mice was blocked by the cyclin D1 antisense construct. These results demonstrate that E2F-1 mediates a Neu-signaling cascade tocyclin D1and identify cyclin D1 as a critical downstream target of neu-induced transformation. |
| Databáze: |
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