The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

Autor: Xiaoman Xu, Bogi Andersen, R Newton, Zhongxian Lu, Ning Wang, Kevin K. Lin, G N Gill, Zhengquan Yu, Kit S. Lam
Rok vydání: 2007
Předmět:
Chromatin Immunoprecipitation
Cancer Research
animal structures
Bone Morphogenetic Protein 7
Histone Deacetylase 2
Apoptosis
Breast Neoplasms
Biology
medicine.disease_cause
Histone Deacetylases
Mice
Mammary Glands
Animal
Downregulation and upregulation
Gene expression
Genetics
medicine
Animals
Humans
Immunoprecipitation
Promoter Regions
Genetic
Molecular Biology
Cells
Cultured
Adaptor Proteins
Signal Transducing
Cell Proliferation
Oligonucleotide Array Sequence Analysis
LIM domain
Homeodomain Proteins
Mice
Knockout
Regulation of gene expression
Gene knockdown
Gene Expression Profiling
Gene Expression Regulation
Developmental
Epithelial Cells
LIM Domain Proteins
DNA-Binding Proteins
Repressor Proteins
Gene expression profiling
Bone Morphogenetic Proteins
embryonic structures
Cancer research
Carcinogenesis
Chromatin immunoprecipitation
Transcription Factors
Zdroj: Oncogene. 26:6431-6441
ISSN: 1476-5594
0950-9232
DOI: 10.1038/sj.onc.1210465
Popis: The nuclear LIM-only protein 4 (LMO4) is upregulated in breast cancer, especially estrogen receptor-negative tumors, and its overexpression in mice leads to hyperplasia and tumor formation. Here, we show that deletion of LMO4 in the mammary glands of mice leads to impaired lobuloalveolar development due to decreased epithelial cell proliferation. With the goal of discovering potential LMO4-target genes, we also developed a conditional expression system in MCF-7 cells for both LMO4 and a dominant negative (DN) form of its co-regulator, cofactor of LIM domains (Clim/Ldb/Nli). We then used DNA microarrays to identify genes responsive to LMO4 and DN-Clim upregulation. One of the genes common to both data sets was bone morphogenic protein 7 (BMP7), whose expression is also significantly correlated with LMO4 transcript levels in a large dataset of human breast cancers, suggesting that BMP7 is a bona fide target gene of LMO4 in breast cancer. Inhibition of BMP7 partially blocks the effects of LMO4 on apoptosis, indicating that BMP7 mediates at least some functions of LMO4. Gene transfer studies show that LMO4 regulates the BMP7 promoter, and chromatin immunoprecipitation studies show that LMO4 and its cofactor Clim2 are recruited to the BMP7 promoter. Furthermore, we demonstrate that HDAC2 recruitment to the BMP7 promoter is inhibited by upregulation of LMO4 and that HDAC2 knockdown upregulates the promoter. These studies suggest a novel mechanism of action for LMO4: LMO4, Clim2 and HDAC2 are part of a transcriptional complex, and increased LMO4 levels can disrupt the complex, leading to decreased HDAC2 recruitment and increased promoter activity.
Databáze: OpenAIRE
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