Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway

Richard J. Lee, Chris Albanese, Maofu Fu, Mark D'Amico, Bing Lin, Genichi Watanabe, George K. Haines, Peter M. Siegel, Mien Chie Hung, Yosef Yarden, Jonathan M. Horowitz, William J. Muller, Richard G. Pestell

Research output: Contribution to journalArticlepeer-review

317 Scopus citations

Abstract

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 to cyclin D1 and identify cyclin D1 as a critical downstream target of neu-induced transformation.

Original languageEnglish
Pages (from-to)672-683
Number of pages12
JournalMolecular and Cellular Biology
Volume20
Issue number2
DOIs
StatePublished - Jan 2000
Externally publishedYes

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