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Title: Identification and characterization of nucleolin as a COUP-TFII coactivator of retinoic acid receptor ýý transcription in breast cancer cells.

Authors: Litchfield, Lacey M; Riggs, Krista A; Hockenberry, Alyson M; Oliver, Laura D; Barnhart, Katelyn G; Cai, Jian; Pierce Jr, William M; Ivanova, Margarita M; Bates, Paula J; Appana, Savitri N; Datta, Susmita; Kulesza, Piotr; McBryan, Jean; Young, Leonie S; Klinge, Carolyn M

Published In PLoS One, (2012)

Abstract: The orphan nuclear receptor COUP-TFII plays an undefined role in breast cancer. Previously we reported lower COUP-TFII expression in tamoxifen/endocrine-resistant versus sensitive breast cancer cell lines. The identification of COUP-TFII-interacting proteins will help to elucidate its mechanism of action as a transcriptional regulator in breast cancer.FLAG-affinity purification and multidimensional protein identification technology (MudPIT) identified nucleolin among the proteins interacting with COUP-TFII in MCF-7 tamoxifen-sensitive breast cancer cells. Interaction of COUP-TFII and nucleolin was confirmed by coimmunoprecipitation of endogenous proteins in MCF-7 and T47D breast cancer cells. In vitro studies revealed that COUP-TFII interacts with the C-terminal arginine-glycine repeat (RGG) domain of nucleolin. Functional interaction between COUP-TFII and nucleolin was indicated by studies showing that siRNA knockdown of nucleolin and an oligonucleotide aptamer that targets nucleolin, AS1411, inhibited endogenous COUP-TFII-stimulated RARB2 expression in MCF-7 and T47D cells. Chromatin immunoprecipitation revealed COUP-TFII occupancy of the RARB2 promoter was increased by all-trans retinoic acid (atRA). RARýý2 regulated gene RRIG1 was increased by atRA and COUP-TFII transfection and inhibited by siCOUP-TFII. Immunohistochemical staining of breast tumor microarrays showed nuclear COUP-TFII and nucleolin staining was correlated in invasive ductal carcinomas. COUP-TFII staining correlated with ERýý, SRC-1, AIB1, Pea3, MMP2, and phospho-Src and was reduced with increased tumor grade.Our data indicate that nucleolin plays a coregulatory role in transcriptional regulation of the tumor suppressor RARB2 by COUP-TFII.

PubMed ID: 22693611 Exiting the NIEHS site

MeSH Terms: Animals; Breast Neoplasms/genetics; Breast Neoplasms/metabolism*; Breast Neoplasms/pathology*; COUP Transcription Factor II/deficiency; COUP Transcription Factor II/genetics; COUP Transcription Factor II/metabolism*; Cell Line, Tumor; Cell Nucleus/drug effects; Cell Nucleus/metabolism; Gene Expression Regulation, Neoplastic/drug effects; Gene Knockdown Techniques; Humans; Neoplasm Grading; Oligodeoxyribonucleotides/pharmacology; Phosphoproteins/chemistry; Phosphoproteins/metabolism*; Promoter Regions, Genetic/drug effects; Promoter Regions, Genetic/genetics; Protein Structure, Tertiary; RNA-Binding Proteins/chemistry; RNA-Binding Proteins/metabolism*; Receptors, Retinoic Acid/genetics*; Repetitive Sequences, Nucleic Acid; Tissue Array Analysis; Transcriptional Activation*/drug effects; Tretinoin/pharmacology

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