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TR3 orphan receptor is expressed in vascular endothelial cells and mediates cell cycle arrest

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Author: Arkenbout, E.K. · Bragt, M. van · Eldering, E. · Bree, C. van · Grimbergen, J.M. · Quax, P.H.A. · Pannekoek, H. · Vries, C.J.M. de
Type:article
Date:2003
Institution: Gaubius Instituut TNO
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 9, 23, 1535-1540
Identifier: 237275
doi: doi:10.1161/01.ATV.0000084639.16462.7A
Keywords: Biology · Biomedical Research · Endothelial cells · TR3 orphan receptor · Vascular biology · Cell nucleus receptor · Cyclin A · Messenger RNA · Mitogen induced nuclear orphan receptor · Nerve growth factor receptor · Nuclear orphan receptor of t cells · Protein · Protein subunit · Receptor subtype · Thymidine · Unclassified drug · Adenovirus · Atherosclerosis · Blood vessel · Controlled study · Down regulation · Endothelium cell · Gene expression · Gene overexpression · Human cell · Medical assessment · Nonhuman · Nucleotide sequence · Protein expression · Smooth muscle fiber · Upregulation · Virus culture · Adenoviridae · Cell Cycle · Cell Division · Cells, Cultured · DNA, Complementary · Endothelium, Vascular · Gene Expression Regulation · Gene Transfer Techniques · Humans · Peptides · Protein Structure, Tertiary · Receptors, Steroid · Receptors, Thyroid Hormone · Sequence Deletion · Stem Cells · Trans-Activation (Genetics) · Umbilical Veins · Variation (Genetics) · Virus Replication

Abstract

Objective - Endothelial cells play a pivotal role in vascular homeostasis. In this study, we investigated the function of the nerve growth factor-induced protein-B (NGFI-B) subfamily of nuclear receptors comprising the TR3 orphan receptor (TR3), mitogen-induced nuclear orphan receptor (MINOR), and nuclear orphan receptor of T cells (NOT) in endothelial cells. Methods and Results - The mRNA expression of TR3, MINOR, and NOT in atherosclerotic lesions was assessed in human vascular specimens. Each of these factors is expressed in smooth muscle cells, as described before, and in subsets of endothelial cells, implicating that they might affect endothelial cell function. Adenoviral overexpression of TR3 in cultured endothelial cells resulted in decreased [ 3H]thymidine incorporation, whereas a dominant-negative TR3 variant that inhibits the activity of endogenous TR3-like factors enhanced DNA synthesis. TR3 interfered with progression of the cell cycle by upregulating p27Kip1 and downregulating cyclin A, whereas expression levels of a number of other cell cycle-associated proteins remained unchanged. Conclusions - These findings demonstrate that TR3 is a modulator of endothelial cell proliferation and arrests endothelial cells in the G1 phase of the cell cycle by influencing cell cycle protein levels. We hypothesize involvement of TR3 in the maintenance of integrity of the vascular endothelium.