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Endostatin causes G1 arrest of endothelial cells through inhibition of cyclin D1. J Biol Chem 2002 May 10;277(19):16464-9

Date

01/30/2002

Pubmed ID

11815623

DOI

10.1074/jbc.M112274200

Abstract

Endostatin, a type XVIII collagen fragment, is a potent antiangiogenic molecule that inhibits endothelial cell migration, promotes apoptosis, and induces cell cycle arrest in vitro. We have investigated the mechanism by which endostatin causes G(1) arrest in endothelial cells. Endostatin decreased the hyperphosphorylated retinoblastoma gene product and down-regulated cyclin D1 mRNA and protein. Importantly, endostatin was unable to arrest cyclin D1 overexpressing endothelial cells, suggesting that cyclin D1 is a critical target for endostatin action. Next, we analyzed cyclin D1 promoter activity in endothelial cells and found that endostatin down-regulated the cyclin D1 promoter. Using a series of deletion and mutant promoter constructs, we identified the LEF1 site in the cyclin D1 promoter as essential for the inhibitory effect of endostatin. Finally, we showed that endostatin can repress cyclin D1 promoter activity in cells over-expressing beta-catenin but not in cells over-expressing a transcriptional activator that functions through the LEF1 site and is insensitive to beta-catenin. Collectively, our data pointed to a role for cyclin D1, and in particular, transcription through the LEF1 site as critical for endostatin action in vitro and suggest that beta-catenin is a target for endostatin.

Author List

Hanai J, Dhanabal M, Karumanchi SA, Albanese C, Waterman M, Chan B, Ramchandran R, Pestell R, Sukhatme VP

Author

Ramani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Angiogenesis Inhibitors
Binding Sites
Cell Cycle
Cells, Cultured
Collagen
Collagen Type XVIII
Cyclin D1
Cytoskeletal Proteins
DNA, Complementary
DNA-Binding Proteins
Dose-Response Relationship, Drug
Down-Regulation
Endostatins
Endothelium, Vascular
G1 Phase
Gene Deletion
Humans
Lymphoid Enhancer-Binding Factor 1
Mutation
Peptide Fragments
Phosphorylation
Promoter Regions, Genetic
Protein Binding
RNA, Messenger
Retinoblastoma Protein
Retroviridae
Time Factors
Trans-Activators
Transcription Factors
Transfection
Umbilical Veins
beta Catenin
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d