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PMID: 10611246 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Molecular and cellular biology ·Vol. 20 ·No. 2 ·2000-01-00 ·Pages 672-83

Lee RJ, Albanese C, Fu M, D'Amico M, Lin B, Watanabe G, Haines GK, Siegel PM, Hung MC, Yarden Y, Horowitz JM, Muller WJ, Pestell RG

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.

MeSH Terms
Animals Binding Sites Carrier Proteins Cell Cycle Proteins Cell Transformation, Neoplastic/pathology Cyclin D1/antagonists & inhibitors,genetics,metabolism DNA-Binding Proteins/metabolism E2F Transcription Factors E2F1 Transcription Factor Humans JNK Mitogen-Activated Protein Kinases MAP Kinase Signaling System Mammary Glands, Animal/metabolism,pathology Mice Mice, Nude Mice, Transgenic Mitogen-Activated Protein Kinases/antagonists & inhibitors,metabolism Monomeric GTP-Binding Proteins/genetics,metabolism Mutation/genetics Promoter Regions, Genetic/genetics Proto-Oncogene Mas RNA, Antisense/genetics,physiology Receptor, ErbB-2/antagonists & inhibitors,genetics,metabolism Retinoblastoma-Binding Protein 1 Sp1 Transcription Factor/metabolism Sp3 Transcription Factor Transcription Factor DP1 Transcription Factors/metabolism Transcriptional Activation Tumor Cells, Cultured
Chemicals
Arid4a protein, mouse Carrier Proteins Cell Cycle Proteins DNA-Binding Proteins E2F Transcription Factors E2F1 Transcription Factor E2F1 protein, human E2f1 protein, mouse MAS1 protein, human Proto-Oncogene Mas RNA, Antisense Retinoblastoma-Binding Protein 1 Sp1 Transcription Factor TFDP1 protein, human Tfdp1 protein, mouse Transcription Factor DP1 Transcription Factors Cyclin D1 Sp3 Transcription Factor Receptor, ErbB-2 JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases Monomeric GTP-Binding Proteins
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Lee R J
Department of Developmental Biology, The Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Albanese C
Fu M
D'Amico M
Lin B
Watanabe G
Haines G K
Siegel P M
Hung M C
Yarden Y
Horowitz J M
Muller W J
Pestell R G
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.20.2.672-683.2000
Published
2000-01-00
Pages
672-83
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC85165
Subset
IM
Grants
NCI NIH HHS · R29CA70897 · United States
NCI NIH HHS · R01 CA075503 · United States
NCI NIH HHS · T32 CA009475 · United States
NCI NIH HHS · R01CA75503 · United States
NIDDK NIH HHS · T32 DK007513 · United States
NCI NIH HHS · P30 CA013330 · United States
NCI NIH HHS · 5-P30-CA13330-26 · United States
External Links
PubMed source DOI: 10.1128/MCB.20.2.672-683.2000 PMC Full Text View journal details
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