title: Nuclear monomeric integrin αv in cancer cells is a coactivator regulated by thyroid hormone.
abstract: Thyroid hormone induces tumor cell and blood vessel cell proliferation via a cell surface receptor on heterodimeric integrin αvβ3. We investigated the role of thyroid hormone-induced internalization of nuclear integrin αv monomer. Physiological concentration of thyroxine (free T4, 10(-10) M), but not 3,5,3'-triiodo-l-thyronine (T3), induced cellular internalization and nuclear translocation of integrin αv monomer in human non-small-cell lung cancer (H522) and ovarian carcinoma (OVCAR-3) cells. T4 did not complex with integrin αv monomer during its internalization. The αv monomer was phosphorylated by activated ERK1/2 when it heterodimerized with integrin β3 in vitro. Nuclear αv complexed with transcriptional coactivator proteins, p300 and STAT1, and with corepressor proteins, NCoR and SMRT. Nuclear αv monomer in T4-exposed cells, but not integrin β3, bound to promoters of specific genes that have important roles in cancer cells, including estrogen receptor-α, cyclooxygenase-2, hypoxia-inducible factor-1α, and thyroid hormone receptor β1 in chromatin immunoprecipitation assay. In summary, monomeric αv is a novel coactivator regulated from the cell surface by thyroid hormone for the expression of genes involved in tumorigenesis and angiogenesis. This study also offers a mechanism for modulation of gene expression by thyroid hormone that is adjunctive to the nuclear hormone receptor (TR)-T3 pathway.
authors: Institute of Cancer Biology and Drug Discovery, Taipei Medical University, 250 Wu-Shin St., Taipei, Taiwan. linhy@tmu.edu.tw
authors: Hung-Yun
authors: HY
authors: Lin
authors: Yee-Fun
authors: YF
authors: Su
authors: Meng-Ti
authors: MT
authors: Hsieh
authors: Sharon
authors: S
authors: Lin
authors: Ran
authors: R
authors: Meng
authors: David
authors: D
authors: London
authors: Cassie
authors: C
authors: Lin
authors: Heng-Yuan
authors: HY
authors: Tang
authors: Jaulang
authors: J
authors: Hwang
authors: Faith B
authors: FB
authors: Davis
authors: Shaker A
authors: SA
authors: Mousa
authors: Paul J
authors: PJ
authors: Davis
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D039482:Integrin alpha5 / Q000737:chemistry / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000737:chemistry / Q000378:metabolism; D039661:Integrin beta3 / Q000737:chemistry / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D055503:Protein Multimerization; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013963:Thyroid Hormones / Q000494:pharmacology*; D013974:Thyroxine / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D039482:Integrin alpha5; D039302:Integrin alphaVbeta3; D039661:Integrin beta3; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D013963:Thyroid Hormones; D014284:Triiodothyronine; D051546:Cyclooxygenase 2; D050880:p300-CBP Transcription Factors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013974:Thyroxine
keywords: angiogenesis; carcinogenesis; gene expression; thyroxine