TY - JOUR TI - Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway AU - Lee, RJ AU - Albanese, C AU - Fu, MF AU - M D'Amico, AU - Lin, B AU - Watanabe, G AU - Haines, GK AU - Siegel, PM AU - Hung, MC AU - Yarden, Y AU - Horowitz, JM AU - Muller, WJ AU - Pestell, RG T2 - MOLECULAR AND CELLULAR BIOLOGY AB - 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 D1 and identify cyclin D1 as a critical downstream target of neu-induced transformation. DA - 2000/1// PY - 2000/1// DO - 10.1128/MCB.20.2.672-683.2000 VL - 20 IS - 2 SP - 672-683 SN - 1098-5549 ER -