title: Differential function and regulation of orphan nuclear receptor TR3 isoforms in endothelial cells.
abstract: TR3 has been reported to be an excellent target for angiogenesis therapies. We reported three TR3 transcript variant messenger RNAs (mRNAs) are expressed in human umbilical vein endothelial cell (HUVEC) and are differentially regulated by vascular endothelial growth factor (VEGF). TR3 transcript variant 1 (TR3-TV1) and variant 2 (TR3-TV2) encoding the same TR3 isoform 1 protein (TR3-iso1) that was named TR3 has been extensively studied. However, the function of TR3 isoform 2 protein (TR3-iso2) encoded by TR3 transcript variant 3 (TR3-TV3) is still not known. Here, we clone and express the novel TR3-iso2 protein and find that expression of TR3-iso2, in contrast to TR3-iso1, inhibits endothelial cell proliferation induced by VEGF-A, histamine, and phorbol-12-myristate-13-acetate (PMA). The differential function of TR3-iso2 correlates with the down-regulation of cyclin D1. However, TR3-iso2 plays similar roles in endothelial cell migration and monolayer permeability as TR3-iso1. We further demonstrate that several intracellular signaling pathways are involved in histamine-induced TR3 transcript variants, including histamine receptor H1-mediated phospholipase C (PLC)/calcium /calcineurin/protein kinase C (PKC)/protein kinase D (PKD) pathway and ERK pathway, as well as histamine receptor H3-mediated PKC-ERK pathway. Further, expressions of TR3-TV1, TR3-TV2, and TR3-TV3 by VEGF and histamine are regulated by different promoters, but not by their mRNA stability.
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.|Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, People's Republic of China.|Department of General Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.|Pancreatic Disease Institute, Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, People's Republic of China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Cui
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.|Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Ji-nan, People's Republic of China.
authors.forename: Shengqiang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.|Department of Obstetrics & Gynecology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, People's Republic of China.
authors.forename: Taiyang
authors.initials: T
authors.lastname: Ye
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.|Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Ji-nan, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.|Department of Medical Oncology & Radiation Oncology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Peng
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.|Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Gengming
authors.initials: G
authors.lastname: Niu
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.|Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Dezheng
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA. hzeng@bidmc.harvard.edu.|Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, 99 Brookline Ave. RN 270F, Boston, MA, 02215, USA. hzeng@bidmc.harvard.edu.
authors.forename: Huiyan
authors.initials: H
authors.lastname: Zeng
mesh_terms: D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D006632:Histamine / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; D006632:Histamine; D013755:Tetradecanoylphorbol Acetate
keywords: Angiogenesis; Cell proliferation; Cell signaling; Migration; TR3/Nur77 transcription variants